Isoindolone derivatives

ABSTRACT

The present invention provides for compounds of formula (I) wherein A, Y, J, R 1 , R 2 , and R 3  have any of the values defined therefor in the specification, and pharmaceutically acceptable salts thereof,that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, diabetes, obesity, cancer, and AIDS. Also provided are pharmaceutical compositions comprising one or more compounds of formula (I).

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Non-Provisional applicationSer. No. 13/796,731 filed on Mar. 12, 2013, and PCT Application No.PCT/CN2012/074411, filed on Apr. 20, 2012, the teachings of which areeach herein incorporated by reference.

BACKGROUND

Bromodomains refer to conserved protein structural folds which bind toN-acetylated lysine residues that are found in some proteins. The BETfamily of bromodomain containing proteins is comprised of four members(BRD2, BRD3, BRD4 and BRDt). Each member of the BET family employs twobromodomains to recognize N-acetylated lysine residues found primarily,but not exclusively, on the amino-terminal tails of histone proteins.These interactions modulate gene expression by recruiting transcriptionfactors to specific genome locations within chromatin. For example,histone-bound BRD4 recruits the transcription factor P-TEFb topromoters, resulting in the expression of a subset of genes involved incell cycle progression (Yang et al., Mol. Cell. Biol. 28: 967-976(2008)). BRD2 and BRD3 also function as transcriptional regulators ofgrowth promoting genes (LeRoy et al., Mol. Cell 30: 51-60 (2008)). BETfamily members were recently established as being important for themaintenance of several cancer types (Zuber et al., Nature 478: 524-528(2011); Mertz et al; Proc. Nat'l. Acad. Sci. 108: 16669-16674 (2011);Delmore et al., Cell 146: 1-14, (2011); Dawson et al., Nature 478:529-533 (2011)). BET family members have also been implicated inmediating acute inflammatory responses through the canonical NF-KBpathway (Huang et al., Mol. Cell. Biol. 29: 1375-1387 (2009)) resultingin the upregulation of genes associated with the production of cytokines(Nicodeme et al., Nature 468: 1119-1123, (2010)). Suppression ofcytokine induction by BET bromodomain inhibitors has been shown to be aneffective approach to treat inflammation-mediated kidney disease in ananimal model (Zhang, et al., J. Biol. Chem. 287: 28840-28851 (2012)).BRD2 function has been linked to predisposition for dyslipidemia orimproper regulation of adipogenesis, elevated inflammatory profiles andincreased susceptibility to autoimmune diseases (Denis, DiscoveryMedicine 10: 489-499 (2010)). The human immunodeficiency virus utilizesBRD4 to initiate transcription of viral RNA from stably integrated viralDNA (Jang et al., Mol. Cell, 19: 523-534 (2005)). BET bromodomaininhibitors have also been shown to reactivate HIV transcription inmodels of latent T cell infection and latent monocyte infection(Banerjee, et al, J. Leukocyte Biol. doi:10.1189/jlb.0312165). BRDt hasan important role in spermatogenesis that is blocked by BET bromodomaininhibitors (Matzuk, et al., Cell 150: 673-684 (2012)). Thus, compoundsthat inhibit the binding of BET family bromodomains to their cognateacetylated lysine proteins are being pursued for the treatment ofcancer, inflammatory diseases, kidney diseases, diseases involvingmetabolism or fat accumulation, and some viral infections, as well asfor providing a method for male contraception. Accordingly, there is anongoing medical need to develop new drugs to treat these indications.

SUMMARY

In one aspect, the present invention relates to compounds of Formula(I), or a pharmaceutically acceptable salt thereof,

-   wherein A is C(R⁸R⁹); Y is C(R⁶R⁷); J is C(R⁴R⁵); R¹ is hydrogen or    C₁-C₃ alkyl; R² is hydrogen or C₁-C₃ alkyl; R³ is heteroaryl, 9 to    12 membered bicyclic aryl, napthalen-1yl, unsubstituted phenyl, or    X, wherein X is

wherein said heteroaryl, 9 to 12 membered bicyclic aryl, ornapthalen-1-yl may be substituted with one to three substituentsindependently selected from the group consisting of NR¹⁶R¹⁸, halo,hydroxyl, C₁-C₃ alkyl, —O-aryl, C₁-C₃ alkylene-aryl, C₁-C₃alkylene-O-aryl, —S-aryl, —O—C₁-C₃ alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl,—NR¹⁶—SO₂—C₁-C₃ haloalkyl, SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl,—C(O)—O—C₁-C₃ alkyl, —C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl),—C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl),—NH—C(O)—C₁-C₃ alkyl, —NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃alkylene-heterocycloalkyl,—O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkylene-C₃-C₁₄cycloalkyl, —O—C₁-C₃ alkylene-heteroaryl, or heteroaryl;

-   wherein X is substituted as set out in (i) or (ii):-   four of R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are hydrogen, and one of R¹⁰,    R¹¹, R¹², R¹³, or R¹⁴ is selected from the following groups:    -   R¹⁰ is NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, C₁-C₃        alkylene-aryl, C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₁-C₃        alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃        haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl,        SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃        alkyl, —C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl),        —C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl),        NH—C(O)—C₁-C₃ alkyl, NH—C(O)-heteroaryl, heterocycloalkyl,        —O—C₁-C₃ alkylene-heterocycloalkyl,—O—C₃-C₁₄ cycloalkyl,        —O—C₁-C₃ alkyleneC₃-C₅ cycloalkyl, C₁-C₃ alkyleneC₇-C₁₄        cycloalkyl, —O—C₁-C₃ alkylene-heteroaryl, or heteroaryl; R¹¹ is        NR¹⁶R¹⁸, fluoro, iodo, bromo, hydroxyl, C₁-C₃ alkyl, —O-aryl,        C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₁-C₃        alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃        haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl,        SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃        alkyl, —C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl),        —C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl),        NH—C(O)—C₁-C₃ alkyl, NH—C(O)-heteroaryl, heterocycloalkyl,        —O—C₁-C₃ alkylene-heterocycloalkyl,—O—C₁-C₃ alkyleneC₃-C₁₄        cycloalkyl, —O—C₁-C₃ alkylene-heteroaryl, or heteroaryl;    -   R¹² is NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, C₁-C₃        alkylene-aryl, C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₂-C₃        alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃        haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl,        SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃        alkyl, —C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl),        —C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl),        NH—C(O)—C₁-C₃ alkyl, NH—C(O)-heteroaryl, heterocycloalkyl,        —O—C₁-C₃ alkylene-heterocycloalkyl, —O—C₃-C₁₄ cycloalkyl,        —O—C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl, —O—C₁-C₃        alkylene-heteroaryl, or heteroaryl;    -   R¹³ and R¹⁴ are NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, —O-aryl,        C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₁-C₃        alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃        haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl,        SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃        alkyl, —C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl),        —C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl),        NH—C(O)—C₁-C₃ alkyl, NH—C(O)-heteroaryl, heterocycloalkyl,        —O—C₁-C₃ alkylene-heterocycloalkyl,—O—C₃-C₁₄ cycloalkyl,        —O—C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl, —O—C₁-C₃        alkylene-heteroaryl, or heteroaryl;-   wherein 5-n of R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are hydrogen, and n of    R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are selected from the following groups:    -   NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, —O-aryl, C₁-C₃        alkylene-aryl, C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₁-C₃        alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃        haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl,        SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃        alkyl, —C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl),        —C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl),        NH—C(O)—C₁-C₃ alkyl, NH—C(O)-heteroaryl, heterocycloalkyl,        —O—C₁-C₃ alkylene-heterocycloalkyl,—O—C₃-C₁₄ cycloalkyl,        —O—C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl, —O—C₁-C₃        alkylene-heteroaryl, or heteroaryl;    -   wherein n is 2, 3, 4 or 5;-   wherein any of said aryl groups of —O-aryl, —S-aryl, C₁-C₃    alkylene-aryl, C₁-C₃ alkylene-O-aryl; said heterocycloalkyl; said    heterocycloalkyl groups of —C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl)    and —O—C₁-C₃ alkylene-heterocycloalkyl; said heteroaryl and said    heteroaryl groups of —C(O)—NH(heteroaryl), NH—C(O)-heteroaryl, and    —O—C₁-C₃ alkylene-heteroaryl; and said cycloalkyl groups of    —O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkyleneC₃-C₅ cycloalkyl, and    —O—C₁-C₃ alkyleneC₃-C₁₄ cycloalkyl may be subsitituted with 1 to 3    subsitituents selected from the group consisting of: halo, C₁-C₃    alkyl, C₁-C₃ haloalkyl, CN, and NR¹⁶R¹⁸; R⁴ and R⁵ are each    independently selected from hydrogen and C₁-C₄ alkyl; R⁶ and R⁷ are    each independently selected from hydrogen and C₁-C₄ alkyl; R⁸ and R⁹    are each independently selected from hydrogen and C₁-C₄ alkyl; and    R¹⁶ and R¹⁸ are each independently selected from hydrogen and C₁-C₃    alkyl. In certain embodiments, R⁴ and R⁵ are hydrogen; and R⁸ and R⁹    are each hydrogen. In certain embodiments, R⁶ and R⁷ are hydrogen;    R⁴ and R⁵ are hydrogen; and R⁸ and R⁹ are each hydrogen. In certain    embodiments, R⁶ and R⁷ are hydrogen. In certain embodiments, R² is    hydrogen. In certain embodiments, R¹ is C₁-C₃ alkyl. In certain    embodiments, R¹ is methyl. In certain embodiments, R¹³ is NR¹⁶R¹⁸,    —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl,    —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl, SO₂—NR¹⁶R¹⁸,    SO₂—C₁-C₃alkyl, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl),    —C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl),    NH—C(O)—C₁-C₃ alkyl, or NH—C(O)-heteroaryl. In certain embodiments,    R¹³ is NR¹⁶R¹⁸, —NR¹⁶—SO₂—C₁-C₃ alkyl, or —NH—SO₂—C₁-C₃ haloalkyl.    In certain embodiments, R³ is heteroaryl, 9 to 12 membered bicyclic    aryl, or napthalen-1-yl. In certain embodiments, R³ is indolyl,    1,3-benzodioxolyl, or benzimidazolyl. In certain embodiments, R³    is X. In certain embodiments, four of R¹⁰, R¹¹, R¹², R¹³, and R¹⁴    are hydrogen, and one of R¹⁰, R¹¹, R¹², R¹³, or R¹⁴ are selected    from the following groups: R¹⁰ is NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃    alkyl, C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₁-C₃    alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃    haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl,    SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃ alkyl,    —C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl), —C(O)—NH(C₁-C₃    alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl), NH—C(O)—C₁-C₃    alkyl, NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃    alkylene-heterocycloalkyl,—O—C₃-C₅ cycloalkyl, —O—C₃-C₅ cycloalkyl,    —O—C₃-C₅ cycloalkyl, —O—C₃-C₅ cycloalkyl, —O—C₃-C₅    cycloalkyl,—O—C₁-C₃ alkyleneC₃-C₅ cycloalkyl, C₁-C₃ alkyleneC₇-C₁₄    cycloalkyl, —O—C₁-C₃ alkylene-heteroaryl, or heteroaryl; R¹¹ is    NR¹⁶R¹⁸, fluoro, iodo, bromo, hydroxyl, C₁-C₃ alkyl, —O-aryl, C₁-C₃    alkylene-aryl, C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₁-C₃    alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃    haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl,    SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃ alkyl,    —C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl), —C(O)—NH(C₁-C₃    alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl), NH—C(O)—C₁-C₃    alkyl, NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃    alkylene-heterocycloalkyl,—O—C₁-C₃ alkyleneC₃-C₁₄ cycloalkyl,    —O—C₁-C₃ alkylene-heteroaryl, or heteroaryl; R¹² is NR¹⁶R¹⁸, halo,    hydroxyl, C₁-C₃ alkyl, C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl,    —S-aryl, —O—C₂-C₃ alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl,    —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl,    —NR¹⁶—SO₂—C₁-C₃ haloalkyl, SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —O—C₁-C₃    alkyl, —C(O)—O—C₁-C₃ alkyl, —C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃    haloalkyl), —C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl),    —C(O)—NH(heteroaryl), NH—C(O)—C₁-C₃ alkyl, NH—C(O)—heteroaryl,    heterocycloalkyl, —O—C₁-C₃ alkylene-heterocycloalkyl,—O—C₃-C₁₄    cycloalkyl, —O—C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl, —O—C₁-C₃    alkylene-heteroaryl, or heteroaryl; R¹³ and R¹⁴ are NR¹⁶R¹⁸, halo,    hydroxyl, C₁-C₃ alkyl, —O-aryl, C₁-C₃ alkylene-aryl, C₁-C₃    alkylene-O-aryl, —S-aryl, —O—C₁-C₃ alkylene-aryl,    —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl,    —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl, SO₂—NR¹⁶R¹⁸,    SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃ alkyl, —C(O)—OH,    —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl), —C(O)—NH(C₁-C₃    alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl), NH—C(O)—C₁-C₃    alkyl, NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃    alkylene-heterocycloalkyl,—O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃    alkylene-C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkylene-heteroaryl, or    heteroaryl; and wherein any of said aryl groups of —O-aryl, —S-aryl,    C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl; said heterocycloalkyl;    said heterocycloalkyl groups of —C(O)—NH(C₁-C₃    alkylene-heterocycloalkyl) and —O—C₁-C₃ alkylene-heterocycloalkyl;    said heteroaryl and said heteroaryl groups of —C(O)—NH(heteroaryl),    NH—C(O)-heteroaryl, and —O—C₁-C₃ alkylene-heteroaryl; and said    cycloalkyl groups of —O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkyleneC₃-C₅    cycloalkyl, and —O—C₁-C₃ alkyleneC₃-C₁₄ cycloalkyl may be    subsitituted with 1 to 3 subsitituents selected from the group    consisting of: halo, C₁-C₃ alkyl, C₁-C₃ haloalkyl, CN, and NR¹⁶R¹⁸.    In certain embodiments, 5-n of R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are    hydrogen, and n of R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are selected from the    following groups: NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, —O-aryl,    C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₁-C₃    alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃    haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl,    SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃ alkyl,    —C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl), —C(O)—NH(C₁-C₃    alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl), NH—C(O)—C₁-C₃    alkyl, NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃    alkylene-heterocycloalkyl,—O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃    alkylene-C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkylene-heteroaryl, or    heteroaryl; wherein n is 2, 3, 4 or 5; wherein any of said aryl    groups of —O-aryl, —S-aryl, C₁-C₃ alkylene-aryl, C₁-C₃    alkylene-O-aryl; said heterocycloalkyl; said heterocycloalkyl groups    of —C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl) and —O—C₁-C₃    alkylene-heterocycloalkyl; said heteroaryl and said heteroaryl    groups of —C(O)—NH(heteroaryl), NH—C(O)-heteroaryl, and —O—C₁-C₃    alkylene-heteroaryl; and said cycloalkyl groups of —O—C₃-C₁₄    cycloalkyl, —O—C₁-C₃ alkylene-C₃-C₅ cycloalkyl, and —O—C₁-C₃    alkylene-C₃-C₁₄ cycloalkyl may be subsitituted with 1 to 3    subsitituents selected from the group consisting of: halo, C₁-C₃    alkyl, C₁-C₃ haloalkyl, CN, and NR^(16 18.) In certain embodiments,    n is 3. In certain embodiments, n is 2. In certain embodiments, R¹³    is NR¹⁶R¹⁸, —NR¹⁶—SO₂—NR—C₁-C₃ alkyl, NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl,    —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl, SO₂—NR¹⁶R¹⁸,    SO₂—C₁-C₃alkyl, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl),    —C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl),    NH—C(O)—C₁-C₃ alkyl, or NH—C(O)-heteroaryl. In certain embodiments,    R¹⁶ is H and R¹⁸ is C₁-C₃ alkyl. In certain embodiments, R¹⁸ is H    and R¹⁶ is C₁-C₃ alkyl. In certain embodiments, R¹⁶ is H and R¹⁸    is H. In certain embodiments, R¹⁶ is C₁-C₃ alkyl and R¹⁸ is C₁-C₃    alkyl. In certain embodiments, R¹³ is NR¹⁶-R¹⁸, and R¹⁶ is hydrogen    and R¹⁸ is hydrogen. In certain embodiments, R¹³ is —NR¹⁶—SO₂—C₁-C₃    alkyl and R¹⁶ is hydrogen. In certain embodiments, R¹³ is    —NR¹⁶—SO₂—C₁-C₃ haloalkyl, and R¹⁶ is hydrogen. In certain    embodiments, R¹³ is NR¹⁶R¹⁸, —NR¹⁶—SO₂—C₁-C₃ alkyl, or —NH—SO₂—C₁-C₃    haloalkyl. In certain embodiments, R¹⁰ is O-aryl. In certain    embodiments, R¹⁰ is O-phenyl or is O-phenyl which is substituted    with 1 to 3 independently groups independently selected from the    group consisting of halo. In certain embodiments, R¹⁰ is    —O-2,4-difluoro-phenyl. In certain embodiments, R¹⁰ is —O—C₁-C₃    alkylene-C₃-C₁₄ cycloalkyl, which may be substituted with 1 to 3    groups independently selected from the group consisting of halo and    C₁-C₃ alkyl. In certain embodiments, R¹⁰ is —O—C₁-C₃ alkylene-C₃-C₁₄    cycloalkyl, which is substituted with 1 to 3 groups independently    selected from the group consisting of halo and C₁-C₃ alkyl. In    certain embodiments, R¹⁰ is —O—C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl,    which is substituted with 1 to 3 groups independently selected from    the group consisting of halo. In certain embodiments, n is 2 and    R¹¹, R¹², and R¹⁴ are hydrogen. In certain embodiments, a compound    of formula I is selected from the group consisting of:    -   3-methyl-1-phenyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-(2-phenoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-(2-aminophenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-(4-methylphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)benzenesulfonamide;    -   1-(2-methoxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-(3,4,5-trimethoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-[4-(methylsulfonyl)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)benzamide;    -   1-(1H-indol-4-yl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-(4-methoxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-(3,4-dimethylphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-(4-chlorophenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-[3-(benzyloxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-(2-chlorophenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-(3,5-dimethylphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-(3-methoxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-(2-{[3-(trifluoromethyl)phenoxy]methyl}phenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-[2-(phenoxymethyl)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-{2-[(2-methylphenoxy)methyl]phenyl}-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-[2-(furan-2-yl)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-(2-hydroxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-[2-(tetrahydrofuran-3-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-[2-(cyclopentylmethoxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-[2-(tetrahydrofuran-2-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-[2-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-{2-[2-(morpholin-4-yl)ethoxy]phenyl}-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-[2-(pyridin-2-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-[2-(quinolin-8-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-[2-(1-benzothiophen-7-ylmethoxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-[2-(pyridin-3-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-[2-(1H-indazol-5-ylmethoxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-(5-amino-2-phenoxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   N-[3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamide;    -   N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamide;    -   N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]acetamide;    -   1-[5-amino-2-(phenylsulfanyl)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   N-[3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-(phenylsulfanyl)phenyl]methanesulfonamide;    -   1-[5-amino-2-(2,4-difluorophenoxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]methanesulfonamide;    -   N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]ethanesulfonamide;    -   N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]-2,2,2-trifluoroethanesulfonamide;    -   N′-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]-N,N-dimethylsulfuric        diamide;    -   N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]acetamide;    -   N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]-1H-pyrrole-2-carboxamide;    -   N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl}ethanesulfonamide;    -   methyl        3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxybenzoate;    -   3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxybenzoic        acid;    -   N-ethyl-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxybenzamide;    -   3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxy-N-(tetrahydrofuran-2-ylmethyl)benzamide;    -   3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxy-N-(1,3-thiazol-2-yl)benzamide;    -   3,6,6-trimethyl-1-phenyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-(2,5-dimethylphenyl)-3,6,6-trimethyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3,6,6-trimethyl-1-[2-(morpholin-4-yl)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-[2-(benzyloxy)phenyl]-3,6,6-trimethyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3,6,6-trimethyl-1-(2-phenoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   N-[3-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]methanesulfonamide;    -   3,6-dimethyl-1-(2-phenoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-(5-amino-2-phenoxyphenyl)-3,6-dimethyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   N-[3-(3,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamide;    -   3-methyl-6-(2-methylpropyl)-1-(2-phenoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   N-{3-[3-methyl-6-(2-methylpropyl)-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl]-4-phenoxyphenyl}methanesulfonamide;    -   3-methyl-1-(2-phenoxyphenyl)-6-(propan-2-yl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   N-{3-[3-methyl-4-oxo-6-(propan-2-yl)-4,5,6,7-tetrahydro-2H-isoindol-1-yl]-4-phenoxyphenyl}methanesulfonamide;    -   N-[3-(3-methyl-4-oxo-6-phenyl-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamide;        and    -   1-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.-   In certain embodiments, a compound of formula I is selected from the    group consisting of:    -   1-(1,3-benzodioxol-5-yl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-[2-(benzyloxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   3-methyl-1-(naphthalen-1-yl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-(1H-benzimidazol-4-yl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   1-(1H-indol-7-yl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;    -   2-[2-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)benzyl]-1H-isoindole-1,3(2H)-dione;        and    -   1-(1,3-benzodioxol-5-yl)-3,6,6-trimethyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.

In another aspect, the present invention relates to pharmaceuticalcompositions comprising a pharmaceutically acceptable excipient and atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to methods of treatingcancer in a subject comprising administering a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptableacceptable salt thereof, to a subject in need thereof. In certainembodiments, the cancer is selected from the group consisting of:acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemia (monocytic, myeloblastic, adenocarcinoma,angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acutet-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladdercancer, brain cancer, breast cancer, bronchogenic carcinoma, cervicalcancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,chronic lymphocytic leukemia, chronic myelocytic (granulocytic)leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor. In certain embodiments, the methods further compriseadministering a therapeutically effective amount of at least oneadditional therapeutic agent.

In another aspect, the present invention relates to methods of treatinga disease or condition in a subject comprising administering atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable acceptable salt thereof, to a subject inneed thereof, wherein said disease or condition is selected from thegroup consisting of: Addison's disease, acute gout, ankylosingspondylitis, asthma, atherosclerosis, Behcet's disease, bullous skindiseases, chronic obstructive pulmonary disease (COPD), Crohn's disease,dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis,hypophysitis, inflammatory bowel disease, Kawasaki disease, lupusnephritis, multiple sclerosis, myocarditis, myositis, nephritis, organtransplant rejection, osteoarthritis, pancreatitis, pericarditis,Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis,psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosingcholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis,toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis,vitiligo, vasculitis, and Wegener's granulomatosis. In certainembodiments, the methods further comprise administering atherapeutically effective amount of at least one additional therapeuticagent. In certain embodiments, the methods further compriseadministering a therapeutically effective amount of at least oneadditional therapeutic agent.

In another aspect, the present invention relates to methods of treatingAIDS in a subject comprising administering a therapeutically effectiveamount of a compound of formula (I), or a pharmaceutically acceptableacceptable salt thereof, to a subject in need thereof. In certainembodiments, the methods further comprise administering atherapeutically effective amount of at least one additional therapeuticagent.

In another aspect, the present invention relates to methods of treatingobesity in a subject comprising administering a therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable acceptable salt thereof, to a subject in need thereof. Incertain embodiments, the methods further comprise administering atherapeutically effective amount of at least one additional therapeuticagent.

In another aspect, the present invention relates to methods of treatingtype II diabetes in a subject comprising administering a therapeuticallyeffective amount of a compound of formula (I), or a pharmaceuticallyacceptable acceptable salt thereof, to a subject in need thereof. Incertain embodiments, the methods further comprise administering atherapeutically effective amount of at least one additional therapeuticagent. In another aspect, the present invention relates to methods oftreating a disease in a subject comprising administering atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable acceptable salt thereof, to a subject inneed thereof, wherein said disease is selected from a disease in one ofthe following groups which consist of:

-   -   cancer;    -   Addison's disease, acute gout, ankylosing spondylitis, asthma,        atherosclerosis, Behcet's disease, bullous skin diseases,        chronic obstructive pulmonary disease (COPD), Crohn's disease,        dermatitis, eczema, giant cell arteritis, glomerulonephritis,        hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki        disease, lupus nephritis, multiple sclerosis, myocarditis,        myositis, nephritis, organ transplant rejection, osteoarthritis,        pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis,        primary biliary cirrhosis, psoriasis, psoriatic arthritis,        rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis,        systemic lupus erythematosus, Takayasu's Arteritis, toxic shock,        thyroiditis, type I diabetes, ulcerative colitis, uveitis,        vitiligo, vasculitis, and Wegener's granulomatosis;    -   diabetic nephropathy, hypertensive nephropathy, HIV-associated        nephropathy, glomerulonephritis, lupus nephritis, IgA        nephropathy, focal segmental glomerulosclerosis, membranous        glomerulonephritis, minimal change disease, polycystic kidney        disease and tubular interstitial nephritis;    -   ischemia-reperfusion induced kidney disease, cardiac and major        surgery induced kidney disease, percutaneous coronary        intervention induced kidney disease, radio-contrast agent        induced kidney disease, sepsis induced kidney disease, pneumonia        induced kidney disease, and drug toxicity induced kidney        disease;    -   AIDS;    -   obesity;    -   type II diabetes; and    -   obesity, dyslipidemia, hypercholesterolemia, Alzheimer's        disease, metabolic syndrome, hepatic steatosis, type II        diabetes, insulin resistance, diabetic retinopathy and diabetic        neuropathy.

DETAILED DESCRIPTION Definitions

It is noted that, as used in this specification and the intended claims,the singular form “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a compound” includes a single compound as well as one or more of thesame or different compounds, reference to “optionally a pharmaceuticallyacceptable carrier” refers to a single optional pharmaceuticallyacceptable carrier as well as one or more pharmaceutically acceptablecarriers, and the like.

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkyl” as used herein, means a saturated, straight or branchedhydrocarbon chain radical. In some instances, the number of carbon atomsin an alkyl moiety is indicated by the prefix “C_(x)-C_(y)”, wherein xis the minimum and y is the maximum number of carbon atoms in thesubstituent. Thus, for example, “C₁-C₆ alkyl” refers to an alkylsubstituent containing from 1 to 6 carbon atoms and “C₁-C₃ alkyl” refersto an alkyl substituent containing from 1 to 3 carbon atoms.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,2,2-dimethylpropyl, 1-methylpropyl, 1-ethylpropyl,1,2,2-trimethylpropyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “alkylene” or “alkylenyl” means a divalent radical derived froma straight or branched, saturated hydrocarbon chain, for example, of 1to 10 carbon atoms or of 1 to 6 carbon atoms (C₁-C₆ alkylene) or of 1 to4 carbon atoms or of 1 to 3 carbon atoms (C₁-C₃ alkylene). Examples ofalkylene and alkylenyl include, but are not limited to, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “C₃-C₁₄ cycloalkyl” (alone or in combination with anotherterm(s)) means a saturated cyclic hydrocarbyl substituent containingfrom 3 to 14 carbon ring atoms. The term cycloalkyl includes monocycliccycloalkyl, bicyclic cycloalkyl, bridged cycloalkyl, and spirocycloalkyl groups. Examples of monocyclic cycloalkyl groups include, butare not limited to, cyclopropyl (cyclopropanyl), cyclobutyl(cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl,cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl, cycloheptyl,cyclooctyl, etc. Unless otherwise indicated, the term “C₃-C₈ monocycliccycloalkyl” refers to monocylic cycloalkyl groups containing from 3 to 8carbons.

In a spirocyclic cycloalkyl group, one atom is common to two differentrings. Examples of spirocyclic cycloalkyls include spiro[2.2]pentanyl,spiro[2.4]heptanyl, and spiro[2.5]octanyl. Unless otherwise indicated,the term “C₅-C₈ spirocyclic cycloalkyl” refers to spirocyclic cycloalkylgroups containing from 5 to 8 carbons.

In a bridged cycloalkyl, the rings share at least two commonnon-adjacent atoms. Examples of bridged cycloalkyls includebicyclo[2.2.1]heptanyl, and adamantanyl. Unless otherwise indicated, theterm “C₇-C₁₀ bridged cycloalkyl” refers to a bridged cycloalkyl groupscontaining from 5 to 10 carbons.

A bicyclic ring cycloalkyl is a C₅-C₇ monocyclic cycloalkyl fused to amonocyclic C₅-C₇ cycloalkyl ring. Non-limiting examples of bicycliccycloalkyls include decahydronaphthalenyl, octahydro-1H-indenyl,octahydropentalenyl, and decahydroazulenyl. The bicyclic cycloalkylgroups may contain one or two alkylene bridges, each consisting of one,two, three, or four carbon atoms in length, and each bridge links twonon-adjacent carbon atoms of the ring system. Non-limiting examples ofbicyclic bridged groups include bicyclo[3.1.1]heptanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.2]nonanyl,bicyclo[3.3.1]nonanyl, and bicyclo[4.2.1]nonanyl,tricyclo[3.3.1.0^(3,7)]nonanyl (octahydro-2,5-methanopentalenyl ornoradamantanyl), and tricyclo[3.3.1.1^(3,7)]decanyl (adamantanyl).

The term “cycloalkenyl” (alone or in combination with another term(s))means a partially saturated cycloalkyl substituent containing from 3 to14 carbon ring atoms. A cycloalkenyl may be a monocyclic carbon ring,which typically contains from 3 to 8 carbon ring atoms (i.e., a C₃-C₈cycloalkenyl) and more typically from 4 to 6 carbon ring atoms (i.e., aC₄-C₆ cycloalkenyl). Examples of single-ring cycloalkenyls includecyclopentenyl, and cyclohexenyl. A cycloalkenyl may alternatively bebicyclic. Examples of bicyclic cycloalkenyls include bridged andspirocyclic cycloalkyls.

The term “heterocycloalkyl” as used herein, means a 3 to 15 memberednon-aromatic monocylic or bicyclic ring radical containing carbon atomsand one to three heteroatoms independently selected from O, N, or S. Thenitrogen and sulfur heteroatoms in the heterocycloalkyl rings mayoptionally be oxidized (e.g. 1,1-dioxidotetrahydrothienyl,1,2-dioxido-1,2-thiazolidinyl, 1,1-dioxidothiomorpholinyl)) and thenitrogen atoms may optionally be quarternized. Unless otherwiseindicated, the foregoing heterocycloalkyls can be C-attached orN-attached where such is possible and which results in the creation of astable structure. For example, piperidinyl can be piperidin-1-yl(N-attached) or piperidin-4-yl (C-attached). Examples ofheterocycloalkyls include 3- to 8-membered monocyclic heterocycloalkyls,8-12 membered bicyclic heterocycloalkyls, and 7-15 membered bridgedbicyclic heterocycloalkyls.

The phrase “3- to 8-membered monocyclic heterocycloalkyl” means anon-aromatic cyclic group having carbon atoms and 1 to 3 heteroatomsindependently selected from S, N or O, wherein when two O atoms or one Oatom and one S atom are present, the two O atoms or one O atom and one Satom are not bonded to each other, respectively. Illustrative examplesof 3- to 8-membered monocyclic heterocycloalkyl include aziridin-1-yl,1-oxa-cyclobutan-2-yl, tetrahydrofuran-3-yl, morpholin-4-yl,2-thiacyclohex-1-yl, 2-oxo-2-thiacyclohex-1-yl,2,2-dioxo-2-thiacyclohex-1-yl, and 4-methyl-piperazin-2-yl.

A “3-membered monocyclic heterocycloalkyl” is a 3-membered, monocycliccycloalkyl ring having 2 carbon atoms and 1 heteroatom selected from thegroup consisting of: 1 O; 1 S; and 1 N. Illustrative examples of3-membered monocyclic heterocycloalkyls include oxiranyl, aziridinyl,and thiiranyl.

A “4-membered monocyclic heterocycloalkyl” is a 4-membered, monocycliccycloalkyl ring having 3 carbon atoms and 1 heteroatom selected from thegroup consisting of: 1 O; 1 S; and 1 N. Illustrative examples of4-membered monocyclic heterocycloalkyls include oxetanyl, azetidinyl,and thietanyl.

A “5-membered monocyclic heterocycloalkyl” is a 5-membered, monocycliccycloalkyl ring having from 1 to 4 carbon atoms and from 1 to 3heteroatoms selected from the group consisting of: 1 O; 1 S; 1 N; 2 N; 3N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1 N; and 1 O and 2 N. Illustrativeexamples of 5-membered monocyclic heterocycloalkyls includetetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl,imidazolidinyl, oxazolidinyl, imidazolinyl, isoxazolidinyl,pyrrolidinyl, 2-pyrrolinyl, and 3-pyrrolinyl.

A “6-membered monocyclic heterocycloalkyl” is a 6-membered, monocycliccycloalkyl ring having from 3 to 5 carbon atoms and from 1 to 3heteroatoms selected from the group consisting of: 1 O; 2 O; 3 O; 1 S; 2S; 3 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 Sand 1 O; 1 S and 2 O; 1 O and 1 N; and 1 O and 2 N. Illustrativeexamples of 6-membered monocyclic heterocycloalkyls includetetrahydropyranyl, dihydropyranyl, dioxanyl, 1,3-dioxolanyl,1,4-dithianyl, hexahydropyrimidine, morpholinyl, piperazinyl,piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl,1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl, thiomorpholinyl,thioxanyl, and trithianyl.

A “7-membered monocyclic heterocycloalkyl” is a 7-membered, monocycliccycloalkyl ring having from 5 or 6 carbon atoms and from 1 to 3heteroatoms selected from the group consisting of: 1 O; 2 O; 1 S; 2 S; 1N; 2 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 10; 1 S and2 O; 1 O and 1 N; and 1 O and 2 N. Illustrative examples of 7-memberedmonocyclic heterocycloalkyls include azepanyl,2,3,4,5-tetrahydro-1H-azepinyl, oxepanyl,2,3,4,5-tetrahydro-1H-oxepinyl, thiepanyl, and2,3,4,5-tetrahydro-1H-thiepinyl.

An “8-membered monocyclic heterocycloalkyl” is a 8-membered, monocycliccycloalkyl ring having from 5 to 7 carbon atoms and from 1 to 3heteroatoms selected from the group consisting of: 1 O; 2 O; 3 O; 1 S; 2S; 3 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 Sand 1O; 1 S and 2 O; 1 O and 1 N; and 1 O and 2 N. Illustrative examplesof 8-membered monocyclic heterocycloalkyls include azocanyl, thiocanyl,oxocanyl, 3,4,5,6-tetrahydro-2H-oxocinyl, etc.

A bicyclic 8-12 membered heterocycloalkyl is a monocyclic 5 to 7membered heterocycloalkyl fused to a phenyl group, or a monocyclic 5 to7 membered heterocycloalkyl fused to a monocyclic C₅-C₇ cycloalkyl, or amonocyclic 5 to 7 membered heterocycloalkyl fused to a monocyclic 5 to 7membered heterocycloalkyl. Representative examples of bicyclicheterocycloalkyls include, but are not limited to, benzopyranyl,benzothiopyranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,2,3-dihydro-1H-indolyl, 3,4-dihydroisoquinolin-2(1H)-yl,2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl,hexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl.

The monocyclic heterocycloalkyl and the bicyclic heterocycloalkyl maycontain one or two alkylene bridges or an alkenylene bridge, or mixturethereof, each consisting of no more than four carbon atoms and eachlinking two non adjacent atoms of the ring system. Examples of suchbridged heterocycloalkyls include, but are not limited to,azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),8-azabicyclo[3.2.1]oct-8-yl, octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane). The term “6- to 9-membered bridgedbicyclic heterocycloalkyl” refers to a ring radical which is eithersaturated or unsaturated, and which is the result of the fusion of 5-,6-, or 7-membered monocyclic heterocycloalkyl to a 3-, 4-, or 5-memberedmonocyclic heterocycloalkyl; or a 5-, 6-, or 7-membered monocyclicheterocycloalkyl to a C₅-C₇-cycloalkyl, wherein the fusion junctionshave 1 to 3 intervening ring atoms. The term “6- to 9-membered bridgedbicyclic heterocycloalkyl” includes saturated and unsaturated “6- to9-membered bridged bicyclic heterocycloalkyls.” “6- to 9-memberedbridged bicyclic heterocycloalkyls” may be substituted as set out abovefor alkyl. Examples of “6- to 9-membered bridged bicyclicheterocycloalkyls” include 3-azabicyclo[4.2.1]nonanyl and7-azabicyclo[2.2.1]heptanyl.

A Spiro heterocycloalkyl is a 7 to 15 membered heterocycloalkyl whereintwo substituents on the same carbon atom of a monocyclic 5 to 7 memberedheterocycloalkyl ring together with said carbon atom form a second ringsystem selected from a monocyclic cycloalkyl, a bicyclic cycloalkyl, amonocyclic heterocycloalkyl, or a bicyclic heterocycloalkyl. Examples ofspiro heterocycloalkyls include, but not limited to,6-azaspiro[2.5]oct-6-yl, 1′H,4H-spiro[1,3-benzodioxine-2,4′-piperidin]-1′-yl, 1′H,3H-spiro[2-benzofuran-1,4′-piperidin]-1′-yl, and1,4-dioxa-8-azaspiro[4.5]dec-8-yl. The monocyclic, the bicyclic, and thespiro heterocycloalkyls can be unsubstituted or substituted. Themonocyclic, the bicyclic and the spiro heterocycloalkyls are connectedto the parent molecular moiety through any carbon atom or any nitrogenatom contained within the ring systems. The nitrogen and sulfurheteroatoms in the heterocycloalkyl rings may optionally be oxidized(e.g. 1,1-dioxidotetrahydrothienyl, 1,2-dioxido-1,2-thiazolidinyl,1,1-dioxidothiomorpholinyl)) and the nitrogen atoms may optionally bequarternized.

An aryl group is an aromatic hydrocarbon radical. Typical aryl groupsinclude phenyl, and naphthyl. In addition, the term “aryl” includes 9 to12 membered bicyclic aryl groups. The term “9 to 12-membered bicyclicaryl” is a radical of a bicyclic group formed by the fusion of a benzenering to: (1) a C₅-C₈ monocyclic cycloalkyl (e.g., indanyl;1,2,3,4-tetrahydro-naphthalenyl;6,7,8,9-tetrahydro-5H-benzocycloheptenyl, etc.); or (2) a 5- to7-membered heterocycloalkyl, which may be substituted with one or twooxo groups (e.g., indolinyl, 1,3-benzodioxolyl, 1,3-dioxoisoindolinyl,isoindolinyl, etc.); wherein the fusion junctions are at adjacentcarbons on the benzene ring.

The term “heteroaryl” as used herein, encompasses monocyclic 5 or 6membered heteroaryls and bicyclic 8 to 12 membered heteroaryls.

A “5-membered heteroaryl” is a 5-membered, monocyclic, aromatic ringradical having from 1 to 4 carbon atoms and from 1 to 4 heteroatomsselected from the group consisting of: 1 O; 1 S; 1 N; 2 N; 3 N; 4 N; 1 Sand 1 N; 1 S and 2 N; 1 O and 1 N; and 1 O and 2 N. Illustrativeexamples of 5-membered heteroaryls include, but are not limited to,furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, oxazolyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, thienyl,2-thienyl, 3-thienyl, tetrazolyl, thiazolyl, thiadiazolyl, andtriazolyl.

A “6-membered heteroaryl” is a 6-membered, monocyclic, aromatic ringradical having from 3 to 5 carbon atoms and from 1 to 3 heteroatomsselected from the group consisting of: 1 N; 2 N; and 3 N. Illustrativeexamples of 6-membered heteroaryls include, but are not limited to,pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or5-pyrimidinyl, pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl,and triazinyl.

An “8- to 12-membered bicyclic heteroaryl” is a ring structure formed bythe fusion of 5- or 6-membered heteroaryl to: (1) an independentlyselected 5-membered heteroaryl; (2) an independently selected 6-memberedheteroaryl (e.g., naphthyridinyl, pteridinyl, phthalazinyl, purinyl,etc.); (3) a C₅-C₈ monocyclic cycloalkyl; (4) a 5- to 7-memberedheterocycloalkyl; or (5) a benzene ring (e.g., benzimidazolyl,benzofuranyl, benzofurazanyl, benzothiazolyl, benzothiophenyl,benzoxazolyl, cinnolinyl, indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl,quinazolinyl, quinoxalinyl, isoindolyl, and isoquinolinyl), wherein thefusion junctions are at adjacent ring atoms. The fusion junctions may beat nitrogen (e.g., indolizine) or carbon atoms in the 5- or 6-memberedheteroaryl.

The term “hydrogen” (alone or in combination with another term(s)) meansa hydrogen radical, and may be depicted as —H.

The term “hydroxy” (alone or in combination with another term(s)) means—OH.

The term “carboxy” (alone or in combination with another term(s)) means—C(O)—OH.

The term “amino” (alone or in combination with another term(s)) means—NH₂.

The term “halogen” or “halo” (alone or in combination with anotherterm(s)) means a fluorine radical (which may be depicted as —F),chlorine radical (which may be depicted as —Cl), bromine radical (whichmay be depicted as —Br), or iodine radical (which may be depicted as—I). The prefix “halo” indicates that the substituent to which theprefix is attached is substituted with one or more independentlyselected halogen radicals. For example, haloalkyl means an alkylsubstituent in which at least one hydrogen radical is replaced with ahalogen radical. Examples of haloalkyls include chloromethyl,1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and1,1,1-trifluoroethyl. It should be recognized that if a substituent issubstituted by more than one halogen radical, those halogen radicals maybe identical or different (unless otherwise stated). Examples ofhaloalkyl include C₁-C₃ haloalkyls, which is a halogenated alkylcontaining from 1 to 3 carbons.

If a moiety is described as “substituted”, a non-hydrogen radical is inthe place of hydrogen radical of any substitutable atom of the moiety.Thus, for example, a substituted heteroaryl moiety is a heteroarylmoiety in which at least one non-hydrogen radical is in the place of ahydrogen radical on the heterocyclic ring. It should be recognized thatif there are more than one substitution on a moiety, each non-hydrogenradical may be identical or different (unless otherwise stated).

If a moiety is described as being “optionally substituted,” the moietymay be either (1) not substituted or (2) substituted. If a moiety isdescribed as being optionally substituted with up to a particular numberof non-hydrogen radicals, that moiety may be either (1) not substituted;or (2) substituted by up to that particular number of non-hydrogenradicals or by up to the maximum number of substitutable positions onthe moiety, whichever is less. Thus, for example, if a moiety isdescribed as a heteroaryl optionally substituted with up to 3non-hydrogen radicals, then any heteroaryl with less than 3substitutable positions would be optionally substituted by up to only asmany non-hydrogen radicals as the heteroaryl has substitutablepositions. To illustrate, tetrazolyl (which has only one substitutableposition) would be optionally substituted with up to one non-hydrogenradical. To illustrate further, if an amino nitrogen is described asbeing optionally substituted with up to 2 non-hydrogen radicals, then aprimary amino nitrogen will be optionally substituted with up to 2non-hydrogen radicals, whereas a secondary amino nitrogen will beoptionally substituted with up to only 1 non-hydrogen radical.

The terms “treat”, “treating”, and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms.

The terms “prevent”, “preventing”, and “prevention” refer to a method ofpreventing the onset of a disease and/or its attendant symptoms orbarring a subject from acquiring a disease. As used herein, “prevent”,“preventing” and “prevention” also include delaying the onset of adisease and/or its attendant symptoms and reducing a subject's risk ofacquiring a disease.

The phrase “therapeutically effective amount” means an amount of acompound, or a pharmaceutically acceptable salt thereof, sufficient toprevent the development of or to alleviate to some extent one or more ofthe symptoms of the condition or disorder being treated whenadministered alone or in conjunction with another pharmaceutical agentor treatment in a particular subject or subject population. For examplein a human or other mammal, a therapeutically effective amount can bedetermined experimentally in a laboratory or clinical setting, or may bethe amount required by the guidelines of the United States Food and DrugAdministration, or equivalent foreign agency, for the particular diseaseand subject being treated.

The term “subject” is defined herein to refer to animals such asmammals, including, but not limited to, primates (e.g., humans), cows,sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

Compounds

Geometric isomers may exist in the present compounds. Compounds of thisinvention may contain carbon-carbon double bonds or carbon-nitrogendouble bonds in the E or Z configuration, wherein the term “E”represents higher order substituents on opposite sides of thecarbon-carbon or carbon-nitrogen double bond and the term “Z” representshigher order substituents on the same side of the carbon-carbon orcarbon-nitrogen double bond as determined by the Cahn-Ingold-PrelogPriority Rules. The compounds of this invention may also exist as amixture of “E” and “Z” isomers. Substituents around a cycloalkyl orheterocycloalkyl may also be designated as being of cis or transconfiguration.

Compounds of this invention may contain asymmetrically substitutedcarbon atoms in the R or S configuration, in which the terms “R” and “S”are as defined by the IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-10.Compounds having asymmetrically substituted carbon atoms with equalamounts of R and S configurations are racemic at those carbon atoms.Atoms with an excess of one configuration over the other are assignedthe configuration present in the higher amount, preferably an excess ofabout 85%-90%, more preferably an excess of about 95%-99%, and stillmore preferably an excess greater than about 99%. Accordingly, thisinvention includes racemic mixtures, relative and absolutestereoisomers, and mixtures of relative and absolute stereoisomers.

Compounds of formula (I) may contain one or more asymmetricallysubstituted atoms. Compounds of formula I may also exist as individualstereoisomers (including enantiomers and diastereomers) and mixturesthereof. Individual stereoisomers of compounds of formula I may beprepared synthetically from commercially available starting materialsthat contain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution of the individual stereoisomer usingmethods that are known to those of ordinary skill in the art. Examplesof resolution are, for example, (i) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography, followed byliberation of the optically pure product; or (ii) separation of themixture of enantiomers or diastereomers on chiral chromatographiccolumns.

Compounds of formula I may also include the various geometric isomersand mixtures thereof resulting from the disposition of substituentsaround a carbon-carbon double bond, a carbon-nitrogen double bond, acycloalkyl group, or a heterocycloalkyl group. Substituents around acarbon-carbon double bond or a carbon-nitrogen double bond aredesignated as being of Z or E configuration and substituents around acycloalkyl or heterocycloalkyl are designated as being of cis or transconfiguration.

Within the present invention it is to be understood that compoundsdisclosed herein may exhibit the phenomenon of tautomerism and alltautomeric isomers are included in the scope of the invention.

Thus, the formula drawings within this specification can represent onlyone of the possible tautomeric, geometric, or stereoisomeric forms. Itis to be understood that the invention encompasses any tautomeric,geometric, or stereoisomeric form, and mixtures thereof, and is not tobe limited merely to any one tautomeric, geometric, or stereoisomericform utilized within the formula drawings.

Isotope Enriched or Labeled Compounds

Compounds of the invention can exist in isotope-labeled or -enrichedform containing one or more atoms having an atomic mass or mass numberdifferent from the atomic mass or mass number most abundantly found innature. Isotopes can be radioactive or non-radioactive isotopes.Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur,fluorine, chlorine, and iodine include, but are not limited to, ²H, ³H,¹³C, 14C, ¹⁵N, ¹⁸O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Compounds thatcontain other isotopes of these and/or other atoms are within the scopeof this invention.

In another embodiment, the isotope-labeled compounds contain deuterium(²H), tritium (³H) or ¹⁴C isotopes. Isotope-labeled compounds of thisinvention can be prepared by the general methods well known to personshaving ordinary skill in the art. Such isotope-labeled compounds can beconveniently prepared by carrying out the procedures disclosed in theExamples disclosed herein and Schemes by substituting a readilyavailable isotope-labeled reagent for a non-labeled reagent. In someinstances, compounds may be treated with isotope-labeled reagents toexchange a normal atom with its isotope, for example, hydrogen fordeuterium can be exchanged by the action of a deuteric acid such asD₂SO₄/D₂O. In addition to the above, relevant procedures andintermediates are disclosed, for instance, in Lizondo, J et al., DrugsFut, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3), 673(1996); Mallesham, Bet al., Org Lett, 5(7), 963 (2003); PCT publicationsWO1997010223, WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos.7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068;7,511,013; and US Patent Application Publication Nos. 20090137457;20090131485; 20090131363; 20090118238; 20090111840; 20090105338;20090105307; 20090105147; 20090093422; 20090088416; and 20090082471, themethods are hereby incorporated by reference.

The isotope-labeled compounds of the invention may be used as standardsto determine the effectiveness of BET bromodomain inhibitors in bindingassays. Isotope containing compounds have been used in pharmaceuticalresearch to investigate the in vivo metabolic fate of the compounds byevaluation of the mechanism of action and metabolic pathway of thenonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3,367-391 (1975)). Such metabolic studies are important in the design ofsafe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal., Advances in Drug Research Vol. 14, pp. 2-36, Academic press,London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut.,36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77,79-88 (1999).

In addition, non-radio active isotope containing drugs, such asdeuterated drugs called “heavy drugs,” can be used for the treatment ofdiseases and conditions related to BET bromodomain activity. Increasingthe amount of an isotope present in a compound above its naturalabundance is called enrichment. Examples of the amount of enrichmentinclude from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25,29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, toabout 100 mol %. Replacement of up to about 15% of normal atom with aheavy isotope has been effected and maintained for a period of days toweeks in mammals, including rodents and dogs, with minimal observedadverse effects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 196084: 770; Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D Met al., Am. J. Physiol. 1961 201: 357). Acute replacement of as high as15%-23% in human fluids with deuterium was found not to cause toxicity(Blagojevic N et al. in “Dosimetry & Treatment Planning for NeutronCapture Therapy”, Zamenhof R, Solares G and Harling O Eds. 1994.Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab.23: 251 (1997)).

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction. While some of the physical properties of astable isotope-labeled molecule are different from those of theunlabeled one, the chemical and biological properties are the same, withone important exception: because of the increased mass of the heavyisotope, any bond involving the heavy isotope and another atom will bestronger than the same bond between the light isotope and that atom.Accordingly, the incorporation of an isotope at a site of metabolism orenzymatic transformation will slow said reactions potentially alteringthe pharmacokinetic profile or efficacy relative to the non-isotopiccompound.

Schemes

Compounds of the present invention (e.g., compounds of Formula I) can beprepared by applying synthetic methodology known in the art andsynthetic methodology outlined in the schemes set forth below. Thecompounds described herein, including compounds of general formula (I)and specific examples, can be prepared, for example, through thereaction schemes depicted in schemes 1-5. The variables A, Y, J, R¹, R²,R³, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ used in the following schemes have themeanings as set forth in the summary and detailed description sections,unless otherwise noted.

Abbreviations used in the descriptions of the schemes and the specificexamples have the following meanings: DME for 1,2-dimethoxyethane, DMFfor dimethylformamide, DMSO for dimethyl sulfoxide, EDAC for1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride; EtOH forethanol; EtOAc for ethyl acetate; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, PdCl₂(PPh₃)₂ forbis(triphenylphosphine)palladium(II) dichloride; Pd₂(dba)₃ fortris(dibenzylideneacetone)dipalladium(0); THF for tetrahydrofuran, TFAfor trifluoroacetic acid, and HPLC for high performance liquidchromatography.

Compounds of general formula (I) may be prepared using general procedureas outlined in Scheme 1. Halides of formula (2) wherein X is Cl, Br, orI may be prepared from halogenation of compounds of formula (1) usinggeneral methodologies for those reactions, for example, by treating (1)with N-bromosuccinimide in a solvent such as, but not limited to,tetrahydrofuran, acetonitrile, or acetone, at a temperature of about−78° C. to 25° C., to provide compounds of formula (2) wherein X is Br.Conversion of (2) to compounds of general formula (I) may be achieved byreaction of (2) with a boronic acid of formula R³B(OH)₂ or derivativethereof (e.g. pinacol ester) under Suzuki coupling conditions (N. Miyamaand A. Suzuki, Chem. Rev. 1995, 95:2457-2483, J. Organomet. Chem. 1999,576:147-148). Generally, the coupling reaction may be conducted in thepresence of a palladium catalyst and a base, and optionally in thepresence of a ligand, and in a suitable solvent at elevated temperature(about 80° C. to about 150° C.). The reaction may be facilitated bymicrowave irradiation. Examples of the palladium catalyst include, butare not limited to, tetrakis(triphenylphosphine)palladium(0),tris(dibenzylideneacetone)dipalladium(0),bis(triphenylphosphine)palladium(II) dichloride, orpalladium(II)acetate. Examples of suitable bases that may be employedinclude, but not limited to, carbonates or phosphates of sodium,potassium, and cesium, and cesium fluoride. Examples of suitable ligandsinclude, but are not limited to,1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante,2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos), or1,1′-bis(diphenylphosphanyl)ferrocene. Non-limiting examples of suitablesolvent include methanol, ethanol, dimethoxyethane,N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydropyran, andwater, or a mixture thereof.

Alternatively, compounds of formula (I) may be synthesized from thereaction of isoindolinone (1) with halides of formula R³X wherein X isBr or I in the presence of a palladium(II) catalyst such asallylpalladium(II) chloride dimer, and in a solvent such as but notlimited to dimethylacetamide or N,N-dimethylformamide at temperaturesranging from about 80° C. to about 150° C.

Compounds of formula (1) wherein R² is hydrogen and R¹ is C₁-C₃ alkylmay be prepared using synthetic routes such as, but not limited to,those illustrated in Scheme 2.

Reaction of compounds of formula (3) wherein R¹ is C₁-C₃ alkyl with2-aminomalonate derivatives (4) wherein R² is hydrogen, in the presenceof sodium acetate and in a solvent such as, but not limited to, aceticacid, provides intermediates of formula (3). The reaction may beconducted at elevated temperature such as, but not limited to, about 80°C. to about 120° C. Ester hydrolysis of (5) followed by decarboxylationof the resulting carboxylic acid affords compounds of formula (1). Forexample, ester hydrolysis may be achieved in the presence of a base suchas, but not limited to, hydroxides of lithium, potassium, or sodium. Thereaction is generally conducted in a solvent such as, but not limitedto, tetrahydrofuran or water, and at temperatures ranging from aboutroom temperature to about 80° C. Heating of the resulting carboxylicacid in an alcoholic solvent (e.g., ethanol), and in the presences of anacid such as, but not limited to, hydrochloric acid or sulfuric acid, ata temperature from about 50° C. to about 100° C. provide compounds offormula (1) wherein R¹ is C₁-C₃ alkyl and R² is hydrogen.

Compounds of formula (I) wherein R³ is a phenyl having an orthosubstituent, OR¹⁰¹, wherein R¹⁰¹ is C₁-C₃ alkyl, aryl, C₁-C₃alkylenyl-aryl, C₁-C₃ alkylenyl-heterocycloalkyl, C₁-C₃alkylenyl-cycloalkyl, or C₁-C₃ alkylenyl-heteroaryl, may be prepared asshown in Scheme 3.

Compounds of formula (7) wherein may be prepared from reaction of (2a)with a boronic acid of formula (6) or derivatives thereof (e.g., pinacolester) using Suzuki coupling conditions as described in Scheme 1.Treatment of the resulting phenols of formula (7) with an appropriatehalide of formula R¹⁰¹X in the presence of a base such as carbonate ofcesium, potassium and sodium, in a solvent such as dimethylformamide ordimethylsulfoxide, and at temperatures ranging from about roomtemperature to about 100° C. provides compounds of formula (10).Alternatively, reaction of phenol (7) with an alcohol of formula R¹⁰¹Hin the presence of triphenylphosphine and in the presence ofdiisopropylazodicarboxylate or diethylazodicarboxylate, in a solventsuch as tetrahydrofuran or dioxane, and at temperatures ranging fromabout room temperature to about 100° C. provides compounds of formula(10).

Alternatively, compounds of formula (10) may be obtained by (a) couplingof (2a) with (8) using reaction conditions described in Scheme 1; and(b) displacement of the fluorine atom of formula (9) with an alcohol offormula R¹⁰¹H. Displacement of the fluorine atom may be accomplished ina solvent such as, but not limited to, dimethylsulfoxide,dimethylformamide, dioxane, or tetrahydrofuran and in the presence of abase such as, but not limited to, carbonate of cesium, potassium, andsodium, or sodium hydride, and at a temperature from about 40° C. toabout 120° C.

Compounds of formula (I) where R¹⁰ is OR¹⁰¹ wherein R¹⁰¹ is as definedabove, and R¹³ is NO₂ may be further derivatized as illustrated inScheme 4.

Reduction of the nitro compounds of formula (11) to the anilines offormula (12). may be achieved using iron powder in the presence ofammonium chloride in a solvent such as, but not limited to,tetrahydrofuran, ethanol, or water, or a mixture thereof, and at atemperature from about 80° C. to about 120° C. Alternatively thisreduction may be carried out with tin chloride in hydrochloric acid at atemperature from about 80° C. to about 120° C. Transformation of (11) to(12) may also be conducted in the presence of a catalyst such asplatinum oxide or palladium on charcoal, in a solvent such as ethanol ormethanol and under hydrogen pressure. Treatment of aniline (12) withsulfonyl chlorides of formula R¹⁰²SO₂Cl wherein R¹⁰² is alkyl orhaloalkyl, in the presence of a base such as triethylamine ordiisopropylethylamine in a solvent such as dichloromethane ortetrahydrofuran and at a temperature from about 0° C. to about 40° C.provides sulfonamides (13).

Treatment of aniline (12) with carboxylic acids of formula R¹⁰³COOHwherein R¹⁰³ is C₁-C₃ alkyl, in the presence of a coupling agent such asHATU or EDAC and a base such as diisopropylethylaminde or triethylamine,and in a solvent such as tetrahydrofuran, dioxane, or dimethylformamide,at a temperature from about 0° C. to about 40° C. provides amides offormula (14).

Compounds of formula (I) wherein R¹⁰ is OR¹⁰¹ and R¹³ isC(O)N(R¹⁰⁴)(R¹⁰⁵) wherein R¹⁰¹ is as defined above, R¹⁰⁴ is hydrogen andR¹⁰⁵ is hydrogen, C₁-C₃ alkyl, -C₁-C₃ alkylene-heterocycloalkyl, orheteroaryl, may be prepared as shown in Scheme 5.

Hydrolysis of the ester moiety of (15) provides acids of formula (16).The hydrolysis step may be carried out in the presence of a base such ashydroxide of lithium, sodium, or potassium, in a solvent such as, butnot limited to, tetrahydrofuran, water, methanol, or dioxane, orcombinations thereof, and at a temperature from about 25° C. to 60° C.Utilizing the amide coupling reaction conditions discussed in Scheme 4,acids of formula (16) may be treated with amines of formula NHR¹⁰⁴R¹⁰⁵to provide amides of formula (17).

It can be appreciated that the synthetic schemes and specific examplesas illustrated in the synthetic examples section are illustrative andare not to be read as limiting the scope of the invention as it isdefined in the appended claims. All alternatives, modifications, andequivalents of the synthetic methods and specific examples are includedwithin the scope of the claims.

Optimum reaction conditions and reaction times for each individual stepcan vary depending on the particular reactants employed and substituentspresent in the reactants used. Specific procedures are provided in theSynthetic Examples section. Reactions can be worked up in theconventional manner, e.g. by eliminating the solvent from the residueand further purified using methodologies for purifying compounds fromreaction mixtures such as, but not limited to, precipitation,crystallization, distillation, extraction, trituration andchromatography.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that can not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups may be used; examples of which can be found in T. Greene and P.Wuts, Protecting Groups in Organic Synthesis (3^(rd) ed.), John Wiley &Sons, NY (1999), which is incorporated herein by reference in itsentirety. Synthesis of the compounds of the invention can beaccomplished by methods analogous to those described in the syntheticschemes described hereinabove and in specific examples.

Starting materials, if not commercially available, can be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound is required, typically itmay be obtained by carrying out one of the procedures described hereinusing an optically active starting material (prepared, for example, byasymmetric induction of a suitable reaction step), or by resolution of amixture of the stereoisomers of the compound or intermediates using astandard procedure (such as chromatographic separation, crystallization,or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound is required, itcan be prepared by carrying out one of the above procedures using a puregeometric isomer as a starting material, or by resolution of a mixtureof the geometric isomers of the compound or intermediates using astandard procedure such as chromatographic separation.

Compounds of formula I can be used in the form of pharmaceuticallyacceptable salts. The phrase “pharmaceutically acceptable salt” meansthose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like andare commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts have been described in S. M. Berge etal. J. Pharmaceutical Sciences, 1977, 66: 1-19.

Compounds of formula (I) may contain either a basic or an acidicfunctionality, or both, and can be converted to a pharmaceuticallyacceptable salt, when desired, by using a suitable acid or base. Thesalts may be prepared in situ during the final isolation andpurification of the compounds of the invention.

Examples of acid addition salts include, but are not limited to acetate,adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, camphorate, camphorsulfonate, digluconate,glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate(isothionate), lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which maybe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts may be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Other examples oforganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, piperazineand the like.

The term “pharmaceutically acceptable prodrug” or “prodrug”as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use.

The present invention contemplates compounds of formula (I) formed bysynthetic means or formed by in vivo biotransformation of a prodrug.

Compounds described herein can exist in unsolvated as well as solvatedforms, including hydrated forms, such as hemi-hydrates. In general, thesolvated forms, with pharmaceutically acceptable solvents such as waterand ethanol among others are equivalent to the unsolvated forms for thepurposes of the invention.

Pharmaceutical Compositions

This invention also provides for pharmaceutical compositions comprisinga therapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier, diluent, or excipient therefor. Thephrase “pharmaceutical composition” refers to a composition suitable foradministration in medical or veterinary use.

The pharmaceutical compositions that comprise a compound of formula (I),alone or or in combination with a second active pharmaceutical agent,may be administered to the subjects orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions as well as sterile powders forreconstitution into sterile injectable solutions or dispersions justprior to use. Examples of suitable aqueous and nonaqueous carriers,diluents, solvents or vehicles include water, ethanol, polyols (such asglycerol, propylene glycol, polyethylene glycol and the like), vegetableoils (such as olive oil), injectable organic esters (such as ethyloleate) and suitable mixtures thereof. Proper fluidity can bemaintained, for example, by the use of coating materials such aslecithin, by the maintenance of the required particle size in the caseof dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents, which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of aparenterally-administered drug form may be accomplished by dissolving orsuspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In certain embodiments, solid dosage formsmay contain from 1% to 95% (w/w) of a compound of formula I. In certainembodiments, the compound of formula I may be present in the soliddosage form in a range of from 5% to 70% (w/w). In such solid dosageforms, the active compound may be mixed with at least one inert,pharmaceutically acceptable excipient or carrier, such as sodium citrateor dicalcium phosphate and/or a) fillers or extenders such as starches,lactose, sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

The pharmaceutical composition may be a unit dosage form. In such formthe preparation is subdivided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampules. Also, the unit dosage form can be a capsule, tablet, cachet, orlozenge itself, or it can be the appropriate number of any of these inpackaged form. The quantity of active component in a unit dosepreparation may be varied or adjusted from 0.1 mg to 1000 mg, from 1 mgto 100 mg, or from 1% to 95% (w/w) of a unit dose, according to theparticular application and the potency of the active component. Thecomposition can, if desired, also contain other compatible therapeuticagents.

The dose to be administered to a subject may be determined by theefficacy of the particular compound employed and the condition of thesubject, as well as the body weight or surface area of the subject to betreated. The size of the dose also will be determined by the existence,nature, and extent of any adverse side-effects that accompany theadministration of a particular compound in a particular subject. Indetermining the effective amount of the compound to be administered inthe treatment or prophylaxis of the disorder being treated, thephysician can evaluate factors such as the circulating plasma levels ofthe compound, compound toxicities, and/or the progression of thedisease, etc. In general, the dose equivalent of a compound is fromabout 1 μg/kg to 100 mg/kg for a typical subject.

For administration, compounds of the formula I can be administered at arate determined by factors that can include, but are not limited to, theLD₅₀ of the compound, the pharmacokinetic profile of the compound,contraindicated drugs, and the side-effects of the compound at variousconcentrations, as applied to the mass and overall health of thesubject. Administration can be accomplished via single or divided doses.

The compounds utilized in the pharmaceutical method of the invention canbe administered at the initial dosage of about 0.001 mg/kg to about 100mg/kg daily. In certain embodiments, the daily dose range is from about0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varieddepending upon the requirements of the subject, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe practitioner. Treatment may be initiated with smaller dosages, whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect undercircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of formula I may also be administered in the form ofliposomes. Liposomes generally may be derived from phospholipids orother lipid substances. Liposomes are formed by mono- or multi-lamellarhydrated liquid crystals which are dispersed in an aqueous medium. Anynon-toxic, physiologically acceptable and metabolizable lipid capable offorming liposomes can be used. The present compositions in liposome formmay contain, in addition to a compound of formula (I), stabilizers,preservatives, excipients and the like. Examples of lipids include, butare not limited to, natural and synthetic phospholipids and phosphatidylcholines (lecithins), used separately or together.

Methods to form liposomes have been described, see example, Prescott,Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.(1976), p. 33 et seq.

Dosage forms for topical administration of a compound described hereininclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Methods of Use

The compounds of formula I, or pharmaceutically acceptable saltsthereof, and pharmaceutical compositions comprising a compound offormula I, or a pharmaceutically acceptable salt thereof, can beadministered to a subject suffering from a bromodomain-mediated disorderor condition. The term “administering” refers to the method ofcontacting a compound with a subject. Thus, the compounds of formula Ican be administered by injection, that is, intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally,parentally, or intraperitoneally. Also, the compounds described hereincan be administered by inhalation, for example, intranasally.Additionally, the compounds of formula I can be administeredtransdermally, topically, via implantation, transdermally, topically,and via implantation. In certain embodiments, the compounds of theformula I may be delivered orally. The compounds can also be deliveredrectally, bucally, intravaginally, ocularly, andially, or byinsufflation. Bromodomain-mediated disorders and conditions can betreated prophylactically, acutely, and chronically using compounds offormula I, depending on the nature of the disorder or condition.Typically, the host or subject in each of these methods is human,although other mammals can also benefit from the administration of acompound of formula I.

A “bromodomain-mediated disorder or condition” is characterized by theparticipation of one or more bromodomains (e.g., BRD4) in the inception,manifestation of one or more symptoms or disease markers, severity, orprogression of a disorder or condition. Accordingly, compounds offormula I may be used to treat cancer, including, but not limited toacoustic neuroma, acute leukemia, acute lymphocytic leukemia, acutemyelocytic leukemia (monocytic, myeloblastic, adenocarcinoma,angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acutet-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladdercancer, brain cancer, breast cancer, bronchogenic carcinoma, cervicalcancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia,chronic lymphocytic leukemia, chronic myelocytic (granulocytic)leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma,glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma,hepatoma, hepatocellular cancer, hormone insensitive prostate cancer,leiomyosarcoma, leukemia, liposarcoma, lung cancer,lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia,lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor.

Further, compounds of formula I may be used to treat inflammatorydiseases, inflammatory conditions, and autoimmune diseases, including,but not limited to: Addison's disease, acute gout, ankylosingspondylitis, asthma, atherosclerosis, Behcet's disease, bullous skindiseases, chronic obstructive pulmonary disease (COPD), Crohn'sdisease,dermatitis, eczema,giant cell arteritis, glomerulonephritis,hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease,lupus nephritis, multiple sclerosis, myocarditis,myositis, nephritis,organ transplant rejection, osteoarthritis, pancreatitis, pericarditis,Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis,psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosingcholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis,toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis,vitiligo, vasculitis, and Wegener's granulomatosis.

Compounds of formula I, or pharmaceutically acceptable salts thereof,may be used to treat AIDS. In addition, compounds of formula I, orpharmaceutically acceptable salts thereof, may be used to treat obesity.Compounds of formula I, or pharmaceutically acceptable salts thereof,may be used to treat type II diabetes.

Compounds of formula I, or pharmaceutically acceptable salts thereof,may be used to treat a disease or condition selected from the groupconsisting of: obesity, dyslipidemia, hypercholesterolemia, Alzheimer'sdisease, metabolic syndrome, hepatic steatosis, type II diabetes,insulin resistance, diabetic retinopathy and diabetic neuropathy.

Compounds of formula I, or pharmaceutically acceptable salts thereof,may be used to provide for contraception in a male subject byadministering a therapeutically effective amount of a compound offormula (I), or a pharmaceutically acceptable acceptable salt thereof.

Compounds of formula I, or pharmaceutically acceptable salts thereof,may be used to treat a chronic kidney disease or condition in a subjectby administering a therapeutically effective amount of a compound offormula (I), wherein said disease or condition is selected from thegroup consisting of: diabetic nephropathy, hypertensive nephropathy,HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgAnephropathy, focal segmental glomerulosclerosis, membranousglomerulonephritis, minimal change disease, polycystic kidney diseaseand tubular interstitial nephritis.

Compounds of formula I, or pharmaceutically acceptable salts thereof,may be used to treat an acute kidney disease or condition in a subjectthat is is selected from the group consisting of: ischemia-reperfusioninduced kidney disease, cardiac and major surgery induced kidneydisease, percutaneous coronary intervention induced kidney disease,radio-contrast agent induced kidney disease, sepsis induced kidneydisease, pneumonia induced kidney disease, and drug toxicity inducedkidney disease.

The compounds of formula I can be co-administered to a subject. The term“co-administered” means the administration of two or more differentpharmaceutical agents or treatments (e.g., radiation treatment) that areadministered to a subject by combination in the same pharmaceuticalcomposition or separate pharmaceutical compositions. Thusco-administration involves administration at the same time of a singlepharmaceutical composition comprising two or more pharmaceutical agentsor administration of two or more different compositions to the samesubject at the same or different times.

The compounds of the invention can be co-administered with atherapeutically effective amount of one or more agents to treat acancer, where examples of the agents include, such as radiation,alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors,apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1) inhibitors,activators of death receptor pathway, Bcr-Abl kinase inhibitors, BiTE(Bi-Specific T cell Engager) antibodies, antibody drug conjugates,biologic response modifiers, cyclin-dependent kinase inhibitors, cellcycle inhibitors, cyclooxygenase-2 inhibitors, DVDs (dual variabledomain antibodies), leukemia viral oncogene homolog (ErbB2) receptorinhibitors, growth factor inhibitors, heat shock protein (HSP)-90inhibitors, histone deacetylase (HDAC) inhibitors, hormonal therapies,immunologicals, inhibitors of inhibitors of apoptosis proteins (IAPB),intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2inhibitors, mammalian target of rapamycin inhibitors, microRNA's,mitogen-activated extracellular signal-regulated kinase inhibitors,multivalent binding proteins, non-steroidal anti-inflammatory drugs(NSAIDs), poly ADP (adenosine diphosphate)-ribose polymerase (PARP)inhibitors, platinum chemotherapeutics, polo-like kinase (Plk)inhibitors, phosphoinositide-3 kinase (bromodomain) inhibitors,proteosome inhibitors, purine analogs, pyrimidine analogs, receptortyrosine kinase inhibitors, etinoids/deltoids plant alkaloids, smallinhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors,ubiquitin ligase inhibitors, and the like, and in combination with oneor more of these agents.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies includeadecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and thelike. Without being limited by theory, one of the mechanisms by whichT-cells elicit apoptosis of the target cancer cell is by exocytosis ofcytolytic granule components, which include perforin and granzyme B. Inthis regard, Bcl-2 has been shown to attenuate the induction ofapoptosis by both perforin and granzyme B. These data suggest thatinhibition of Bcl-2 could enhance the cytotoxic effects elicited byT-cells when targeted to cancer cells (V. R. Sutton, D. L. Vaux and J.A. Trapani, J. of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′- and/ or the3′-ends of a given strand.

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site. Multispecific DVDs include DVD bindingproteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide,decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide,KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol,mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine,temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamideand the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN®(melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitorsand pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((−)gossypol), GENASENSE® (G3139or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194,IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax), ABT-199, and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include EGFR antibodies, ABX-EGF, anti-EGFRimmunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgAantibodies, IRESSA® (gefltinib), TARCEVA® (erlotinib or OSI-774), TP-38,EGFR fusion protein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-l9Am SGN-35,SGN-75 and the like

Activators of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death receptors (e.g., DR4 and DR5) such asApomab, conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029,LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3specific antibodies, BSG2 specific antibodies, DLL4 specific antibodiesand C-met specific antibodies, and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20antibodies types I and II and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™(fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate,MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1,combinations thereof and the like. Other agents includeALFAFERONE®,(IFN-α), BAM-002 (oxidized glutathione), BEROMUN®(tasonermin), BEXXAR® (tositumomab), CAMPATH® (alemtuzumab), CTLA4(cytotoxic lymphocyte antigen 4), decarbazine, denileukin, epratuzumab,GRANOCYTE® (lenograstim), lentinan, leukocyte alpha interferon,imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitumomab,molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN® (filgrastim),OncoVAC-CL, OVAREX® (oregovomab), pemtumomab (Y-muHMFG1), PROVENGE®(sipuleucel-T), sargaramostim, sizofilan, teceleukin, THERACYS®(Bacillus Calmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic,Lorus Pharmaceuticals), Z-100 (Specific Substance of Maruyama (SSM)),WF-10 (Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomabtiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofiran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins,NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers thatenhance the efficacy of radiotherapy. Examples of radiotherapy includeexternal beam radiotherapy, teletherapy, brachytherapy and sealed,unsealed source radiotherapy and the like.

Additionally, compounds having Formula (I) may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA),APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin,L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene),AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine),CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EPO906 (epithilone B), GARDASIL® (quadrivalent human papillomavirus(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®,GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine),halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101,IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT®(AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zorubicin and the like.

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents to treat aninflammatory disease or condition, or autoimmune disease, where examplesof the agents include, such as methotrexate, 6-mercaptopurine,azathioprine sulphasalazine, mesalazine, olsalazinechloroquinine/hydroxychloroquine, pencillamine, aurothiomalate(intramuscular and oral), azathioprine, cochicine, corticosteroids(oral, inhaled and local injection), beta-2 adrenoreceptor agonists(salbutamol, terbutaline, salmeteral), xanthines (theophylline,aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium andoxitropium, cyclosporin, FK506, rapamycin, mycophenolate mofetil,leflunomide, NSAIDs, for example, ibuprofen, corticosteroids such asprednisolone, phosphodiesterase inhibitors, adensosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents, agentswhich interfere with signalling by proinflammatory cytokines such asTNFα or IL-1 (e.g., NIK, IKK, p38 or MAP kinase inhibitors), IL-1βconverting enzyme inhibitors, T-cell signalling inhibitors such askinase inhibitors, metalloproteinase inhibitors, sulfasalazine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors and the derivatives p75TNFRIgG (etanercept) and p55TNFRIgG(Lenercept), sIL-1RI, sIL-1RII, sIL-6R), antiinflammatory cytokines(e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ), celecoxib, folic acid,hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen,valdecoxib, sulfasalazine, methylprednisolone, meloxicam,methylprednisolone acetate, gold sodium thiomalate, aspirin,triamcinolone acetonide, propoxyphene napsylate/apap, folate,nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium,oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenacsodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate,sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronatesodium, prednisolone, morphine sulfate, lidocaine hydrochloride,indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl,sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol,naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP,MRA, CTLA4-IG, IL-18 BP, anti-IL-12, Anti-ILLS, BIRB-796, SCIO-469,VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, S1P1 agonists(such as FTY720), PKC family inhibitors (such as Ruboxistaurin orAEB-071) and Mesopram. In certain embodiments, combinations includemethotrexate or leflunomide and in moderate or severe rheumatoidarthritis cases, cyclosporine and anti-TNF antibodies as noted above.

Non-limiting examples of therapeutic agents for inflammatory boweldisease with which a compound of Formula (I) of the invention may beco-administered include the following: budenoside; epidermal growthfactor; corticosteroids; cyclosporin, sulfasalazine; aminosalicylates;6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors;mesalamine; olsalazine; balsalazide; antioxidants; thromboxaneinhibitors; IL-1 receptor antagonists; anti-IL-1β monoclonal antibodies;anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors;pyridinyl-imidazole compounds; antibodies to or antagonists of otherhuman cytokines or growth factors, for example, TNF, LT, IL-1, IL-2,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, IL-23, EMAP-II, GM-CSF, FGF, andPDGF; cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28,CD30, CD40, CD45, CD69, CD90 or their ligands; methotrexate;cyclosporine; FK506; rapamycin; mycophenolate mofetil; leflunomide;NSAIDs, for example, ibuprofen; corticosteroids such as prednisolone;phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents;complement inhibitors; adrenergic agents; agents which interfere withsignalling by proinflammatory cytokines such as TNFα or IL-1 (e.g. NIK,IKK, or MAP kinase inhibitors); IL-1β converting enzyme inhibitors; TNFαconverting enzyme inhibitors; T-cell signalling inhibitors such askinase inhibitors; metalloproteinase inhibitors; sulfasalazine;azathioprine; 6-mercaptopurines; angiotensin converting enzymeinhibitors; soluble cytokine receptors and derivatives thereof (e.g.soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) andantiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ).Preferred examples of therapeutic agents for Crohn's disease with whicha compound of Formula (I) can be combined include the following: TNFantagonists, for example, anti-TNF antibodies, D2E7 (adalimumab), CA2(infliximab), CDP 571, TNFR-Ig constructs, (p75TNFRIgG (etanercept) andp55TNFRIgG (LENERCEPT^(TM)) inhibitors and PDE4 inhibitors. A compoundof Formula (I) can be combined with corticosteroids, for example,budenoside and dexamethasone; sulfasalazine, 5-aminosalicylic acid;olsalazine; and agents which interfere with synthesis or action ofproinflammatory cytokines such as IL-1, for example, IL-1β convertingenzyme inhibitors and IL-1ra; T cell signaling inhibitors, for example,tyrosine kinase inhibitors; 6-mercaptopurine; IL-11; mesalamine;prednisone; azathioprine; mercaptopurine; infliximab; methylprednisolonesodium succinate; diphenoxylate/atrop sulfate; loperamide hydrochloride;methotrexate; omeprazole; folate; ciprofloxacin/dextrose-water;hydrocodone bitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole; thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis withwhich a compound of Formula (I) may be co-administered include thefollowing: corticosteroids; prednisolone; methylprednisolone;azathioprine; cyclophosphamide; cyclosporine; methotrexate;4-aminopyridine; tizanidine; interferon-β1a (AVONEX®; Biogen);interferon-β1b (BETASERON®; Chiron/Berlex); interferon α-n3) (InterferonSciences/Fujimoto), interferon-α (Alfa Wassermann/J&J), interferonβ1A-IF (Serono/Inhale Therapeutics), Peginterferon α 2b(Enzon/Schering-Plough), Copolymer 1 (Cop-1; COPAXONE®; TevaPharmaceutical Industries, Inc.); hyperbaric oxygen; intravenousimmunoglobulin; cladribine; antibodies to or antagonists of other humancytokines or growth factors and their receptors, for example, TNF, LT,IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15, IL-16, EMAP-II,GM-CSF, FGF, and PDGF. A compound of Formula (I) can be combined withantibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD19,CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or theirligands. A compound of Formula (I) may also be combined with agents suchas methotrexate, cyclosporine, FK506, rapamycin, mycophenolate mofetil,leflunomide, an S1P1 agonist, NSAIDs, for example, ibuprofen,corticosteroids such as prednisolone, phosphodiesterase inhibitors,adensosine agonists, antithrombotic agents, complement inhibitors,adrenergic agents, agents which interfere with signalling byproinflammatory cytokines such as TNFα or IL-1 (e.g., NIK, IKK, p38 orMAP kinase inhibitors), IL-1β converting enzyme inhibitors, TACEinhibitors, T-cell signaling inhibitors such as kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, azathioprine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines(e.g. IL-4, IL-10, IL-13 and TGFβ).

A compound of Formula (I) may also be co-administered with agents, suchas alemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliprodenhydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol,α-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptorantagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulatedmitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidoneallotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2,tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler,Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for ankylosing spondylitiswith which a compound of Formula (I) can be co-administered include thefollowing: ibuprofen, diclofenac, misoprostol, naproxen, meloxicam,indomethacin, diclofenac, celecoxib, rofecoxib, sulfasalazine,methotrexate, azathioprine, minocyclin, prednisone, and anti-TNFantibodies, D2E7 (HUMIRA®), CA2 (infliximab), CDP 571, TNFR-Igconstructs, (p75TNFRIgG (ENBREL®) and p55TNFRIgG (LENERCEPT®).

Non-limiting examples of therapeutic agents for asthma with which acompound of Formula (I) may be co-administered include the following:albuterol, salmeterol/fluticasone, montelukast sodium, fluticasonepropionate, budesonide, prednisone, salmeterol xinafoate, levalbuterolHCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate,triamcinolone acetonide, beclomethasone dipropionate, ipratropiumbromide, azithromycin, pirbuterol acetate, prednisolone, theophyllineanhydrous, methylprednisolone sodium succinate, clarithromycin,zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillintrihydrate, flunisolide, allergy injection, cromolyn sodium,fexofenadine hydrochloride, flunisolide/menthol,amoxicillin/clavulanate, levofloxacin, inhaler assist device,guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl,doxycycline hyclate, guaifenesin/d-methorphan,p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride,mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin,pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed,phenylephrine/cod/promethazine, codeine/promethazine, cefprozil,dexamethasone, guaifenesin/pseudoephedrine,chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate,epinephrine, methylprednisolone, anti-IL-13 antibody, and metaproterenolsulfate.

Non-limiting examples of therapeutic agents for COPD with which acompound of Formula (I) may be co-administered include the following:albuterol sulfate/ipratropium, ipratropium bromide,salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasonepropionate, prednisone, theophylline anhydrous, methylprednisolonesodium succinate, montelukast sodium, budesonide, formoterol fumarate,triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin,beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxonesodium, amoxicillin trihydrate, gatifloxacin, zafirlukast,amoxicillin/clavulanate, flunisolide/menthol,chlorpheniramine/hydrocodone, metaproterenol sulfate,methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorphenir,pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate,tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.

Non-limiting examples of therapeutic agents for psoriasis with which acompound of Formula (I) may be co-administered include the following:calcipotriene, clobetasol propionate, triamcinolone acetonide,halobetasol propionate, tazarotene, methotrexate, fluocinonide,betamethasone diprop augmented, fluocinolone acetonide, acitretin, tarshampoo, betamethasone valerate, mometasone furoate, ketoconazole,pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea,betamethasone, clobetasol propionate/emoll, fluticasone propionate,azithromycin, hydrocortisone, moisturizing formula, folic acid,desonide, pimecrolimus, coal tar, diflorasone diacetate, etanerceptfolate, lactic acid, methoxsalen, he/bismuth subgal/znox/resor,methylprednisolone acetate, prednisone, sunscreen, halcinonide,salicylic acid, anthralin, clocortolone pivalate, coal extract, coaltar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone,diazepam, emollient, fluocinonide/emollient, mineral oil/castor oil/nalact, mineral oil/peanut oil, petroleum/isopropyl myristate, psoralen,salicylic acid, soap/tribromsalan, thimerosal/boric acid, celecoxib,infliximab, cyclosporine, alefacept, efalizumab, tacrolimus,pimecrolimus, PUVA, UVB, sulfasalazine, ABT-874 and ustekinamab.

Non-limiting examples of therapeutic agents for psoriatic arthritis withwhich a compound of Formula (I) may be co-administered include thefollowing: methotrexate, etanercept, rofecoxib, celecoxib, folic acid,sulfasalazine, naproxen, leflunomide, methylprednisolone acetate,indomethacin, hydroxychloroquine sulfate, prednisone, sulindac,betamethasone diprop augmented, infliximab, methotrexate, folate,triamcinolone acetonide, diclofenac, dimethylsulfoxide, piroxicam,diclofenac sodium, ketoprofen, meloxicam, methylprednisolone,nabumetone, tolmetin sodium, calcipotriene, cyclosporine, diclofenacsodium/misoprostol, fluocinonide, glucosamine sulfate, gold sodiumthiomalate, hydrocodone bitartrate/apap, ibuprofen, risedronate sodium,sulfadiazine, thioguanine, valdecoxib, alefacept, D2E7 (adalimumab), andefalizumab.

Preferred examples of therapeutic agents for SLE (Lupus) with which acompound of Formula (I) may be co-administered include the following:NSAIDS, for example, diclofenac, naproxen, ibuprofen, piroxicam,indomethacin; COX2 inhibitors, for example, celecoxib, rofecoxib,valdecoxib; anti-malarials, for example, hydroxychloroquine; steroids,for example, prednisone, prednisolone, budenoside, dexamethasone;cytotoxics, for example, azathioprine, cyclophosphamide, mycophenolatemofetil, methotrexate; inhibitors of PDE4 or purine synthesis inhibitor,for example Cellcept®. A compound of Formula (I) may also be combinedwith agents such as sulfasalazine, 5-aminosalicylic acid, olsalazine,Imuran® and agents which interfere with synthesis, production or actionof proinflammatory cytokines such as IL-1, for example, caspaseinhibitors like IL-1β converting enzyme inhibitors and IL-1ra. Acompound of Formula (I) may also be used with T cell signalinginhibitors, for example, tyrosine kinase inhibitors; or molecules thattarget T cell activation molecules, for example, CTLA-4-IgG or anti-B7family antibodies, anti-PD-1 family antibodies. A compound of Formula(I) can be combined with IL-11 or anti-cytokine antibodies, for example,fonotolizumab (anti-IFNg antibody), or anti-receptor receptorantibodies, for example, anti-IL-6 receptor antibody and antibodies toB-cell surface molecules. A compound of Formula (I) may also be usedwith LJP 394 (abetimus), agents that deplete or inactivate B-cells, forexample, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlySantibody), TNF antagonists, for example, anti-TNF antibodies, D2E7(adalimumab), CA2 (infliximab), CDP 571, TNFR-Ig constructs, (p75TNFRIgG(etanercept) and p55TNFRIgG (LENERCEPT™).

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents used in theprevention or treatment of AIDS, where examples of the agents include,HIV reverse transcriptase inhibitors, HIV protease inhibitors,immunomodulators, and other retroviral drugs. Examples of reversetranscriptase inhibitors include, but are not limited to, abacavir,adefovir, didanosine, dipivoxil delavirdine, efavirenz, lamivudine,nevirapine, stavudine zalcitabine, and zidovudine. Examples of proteaseinhibitors include, but are not limited to, amprenavir, indinavir,lopinavir, nelfinavir, ritonavir, and saquinavir.

A compound of Formula (I) may also be co-administered with insulin forthe treatment of type I diabetes.

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents used in theprevention or treatment of AIDS, where examples of the agents include,HIV reverse transcriptase inhibitors, HIV protease inhibitors,immunomodulators, and other retroviral drugs. Examples of reversetranscriptase inhibitors include, but are not limited to, abacavir,adefovir, didanosine, dipivoxil delavirdine, efavirenz, emtricitabine,lamivudine, nevirapine, rilpivirine, stavudine, tenofovir, zalcitabine,and zidovudine. Examples of protease inhibitors include, but are notlimited to, amprenavir, atazanavir, darunavir, indinavir, fosamprenavir,lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. Examplesof other retroviral drugs include, but are not limited to, elvitegravir,enfuvirtide, maraviroc and raltegravir.

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents used in thetreatment of obesity, where examples of the agents include orlistat.

The compounds of the invention can also be co-administered with atherapeutically effective amount of one or more agents used in thetreatment of type II diabetes, where examples of the agents include,alpha glucosidase inhibitors, insulin, metformin, sulfonylureas (e.g.,carbutamide, acetohexamide, chlorpropamide, glibenclamide, glibornuride,gliclazide, glimepiride, glipizide, gliquidone, glisoxepide,glyclopyramide, tolbutamide, and tolazamide), nonsulfonylureas (e.g.,nateglinide, and repaglinide), and thiazolidinediones (e.g.,pioglitazone).

The compounds of the invention can be co-administered with atherapeutically effective amount of one or more agents to prevent ortreat type II diabetes, hepatic steatosis, insulin resistance, metabolicsyndrome and related disorders, where examples of the agents include,but are not limited to, insulin and insulins that have been modified toimprove the duration of action in the body; agents that stimulateinsulin secretion such as acetohexamide, chlorpropamide, glyburide,glimepiride, glipizide, glicazide, glycopyramide, gliquidone,rapaglinide, nataglinide, tolazamide and tolbutamide; agents that areglucagon-like peptide agonists such as exanatide, liraglutide andtaspoglutide; agents that inhibit dipeptidyl-peptidase IV such asvildagliptin, sitagliptin, saxagliptin, linagliptin, allogliptin andseptagliptin; agents that bind to the peroxisome proliferator-activatedreceptor gamma such as rosiglitazone and pioglitazone; agents thatdecrease insulin resistance such as metformin; agents that reduceglucose absorbance in the small intestine such as acarbose, miglitol andvoglibose.

The compounds of the invention can be co-administered with atherapeutically effective amount of one or more agents to prevent ortreat acute kidney disorders and chronic kidney diseases, where examplesof the agents include, but are not limited to, dopamine, diuretics suchas furosemide, bumetanide, thiazide and the like, mannitol, calciumgluconate, sodium bicarbonate, albuterol, paricalcitol, doxercalciferol,and cinacalcet.

The following Examples may be used for illustrative purposes and shouldnot be deemed to narrow the scope of the invention.

EXAMPLES Example 13-methyl-1-phenyl-2,5,6,7-tetrahydro-4H-isoindol-4-one Example 1a

1-bromo-3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one. A 50 mL roundbottomflask with stirbar was charged with3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one (Clezy, P. S.; Fookes, C. J.R.; Mirza, A. H. Aust. J. Chem. 1977, 30, 1337-47.) (0.502 g, 3.36 mmol)in tetrahydrofuran (8 mL) and cooled to −78° C. under nitrogen.Recrystallized N-bromo succinimide (0.608 g, 3.42 mmol) was added andthe mixture stirred for 30 minutes. The reaction mixture was poured intoa separatory funnel containing aqueous sodium sulfite and extracted into100 mL ether. The organics were washed with aqueous sodium bicarbonateand dried over anhydrous sodium sulfate. The crude material was adsorbedon silica gel and chromatographed on a 40 g silica cartridge elutingwith 10-100% ethyl acetate/hexanes to provide the title compound.

Example 1b

3-methyl-1-phenyl-2,5,6,7-tetrahydro-4H-isoindol-4-one. A 5 mL microwavereaction vessel equipped with stirbar was charged with Example 1a(0.0556 g, 0.244 mmol), phenylboronic acid (0.030 g, 0.244 mmol), 2 Maqueous sodium carbonate (1.5 mL, 3.00 mmol) andbis(triphenylphosphine)palladium(II) dichloride (0.171 g, 0.244 mmol) inethanol (1.2 mL)/DME (1.2 mL) and sealed. The mixture was heated to 120°C. for 30 minutes in a Biotage Initiator 2 monomode microwave reactor,then cooled to ambient temperature. The mixture was shaken in areparatory funnel with 50 mL ethyl acetate and 50 mL water. The organicswere dried over anhydrous sodium sulfate. After filtration and solventremoval the residue was purified by reverse phase HPLC (C18, 0-100%CH₃CN/water (0.1% TFA)) to afford the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 11.51 (bs, 1H), 7.50-7.38 (m, 4H), 7.21 (t, J=7.12 Hz, 1H),2.79 (t, J=6.10 Hz, 2H), 2.51 (s, 3H), 2.33 (m, 2H), 1.94 (m, 2H). MS(DCI+) m/z 226.1 (M+H)⁻, 243.1 (M+NH₄)⁺.

Example 2

3-methyl-1-(2-phenoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 2 was prepared according to the procedure similar to that usedfor the preparation of Example 1b, substituting 2-phenoxyphenylboronicacid for phenylboronic acid, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 11.34 (bs, 1H), 7.42 (dd, J=7.54, 1.59 Hz, 1H), 7.31 (m,3H), 7.23 (m, 1H), 7.06 (t, J=7.34 Hz, 1H), 6.93 (m, 3H), 2.59 (m, 1H),2.54 (s, 3H), 2.26 (m, 2H), 1.85 (m, 2H). MS (ESI+) m/z 318.2 (M+H)⁺.

Example 3

1-(2-aminophenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one. Example3 was prepared according to the procedure similar to that used for thepreparation of Example 1b, substituting 2-aminophenylboronic acid forphenylboronic acid, to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 11.28 (bs, 1H), 7.17-7.10 (m, 2H), 6.92 (d, J=6.4 Hz, 1H),6.83 (t, J=7.1 Hz, 1H), 2.56 (t, J=6.15 Hz, 2H), 2.44 (s, 3H), 2.29 (m,2H), 1.89 (m, 2H). MS (DCI+) m/z 241.1 (M+H)⁻, 258.1 (M+NH₄)⁻.

Example 4

3-methyl-1-(4-methylphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one. A 4mLvial was charged with a stirbar, a solution of Example 1a (20 mg, 0.088mmol) in ethanol (1 mL), a solution of p-tolylboronic acid (16 mg, 1.2eq, 0.105 mmol) in ethanol (1 mL), an aqueous solution of 1M Cs₂CO₃ (180μL, 2.0 eq, 0.18 mmol), and SiliaCat DPP-Pd resin (Silicycle, Inc.) (32mg, 0.10 equivalent, 0.27 mmol/g loading). The vial was capped andplaced in Anton Paar Synthos 3000 parallel microwave synthesizer at 120°C. for 30 minutes. Upon completion the crude material was filtered,dried, and purified by reverse phase HPLC (C18, 0-100% CH₃CN/water (0.1%TFA)) to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 11.45(bs, 1H), 7.37 (d, J=8.24 Hz, 2H), 7.21 (d, J=8.24 Hz, 2H), 2.76 (t,J=6.10 Hz, 2H), 2.46 (s, 3H), 2.32 (m, 2H), 2.31 (s, 3H), 1.93 (m, 2H).MS (ESI+) m/z 240.1 (M+H)⁺.

Example 5

4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)benzenesulfonamide.Example 5 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substituting4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide forp-tolylboronic acid, to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 7.85 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 2.84 (t,J=6.1 Hz, 2H), 2.50 (s, 3H), 2.37 (m, 2H), 1.97 (m, 2H). MS (ESI+) m/z305.2 (M+H)⁺.

Example 6

1-(2-methoxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 6 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substituting 2-methoxyphenylboronicacid for p-tolylboronic acid, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 11.19 (bs, 1H), 7.27 (m, 2H), 7.08 (d, J=7.93 Hz, 1H),7.00 (t, J=7.48 Hz, 1H), 3.80 (s, 3H), 2.58 (t, J=6.10 Hz, 2H), 2.46 (s,3H), 2.33 (m, 2H), 1.89 (m, 2H). MS (ESI+) m/z 256.1 (M+H)⁻.

Example 7

3-methyl-1-(3,4,5-trimethoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 7 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substituting3,4,5-trimethoxyphenylboronic acid for p-tolylboronic acid, to providethe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 6.73 (s, 2H), 3.83 (s,6H), 3.68 (s, 3H), 2.82 (t, J=5.95 Hz, 2H), 2.49 (s, 3H), 2.35 (m, 2H),1.95 (m, 2H). MS (ESI+) m/z 316.2 (M+H)⁺.

Example 8

3-methyl-1-[4-(methylsulfonyl)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 8 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substituting4-(methylsulfonyl)phenylboronic acid for p-tolylboronic acid, to providethe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 7.93 (d, J=8.54 Hz, 2H),7.72 (d, J=8.54 Hz, 2H), 3.21 (s, 3H), 2.86 (t, J=6.10 Hz, 2H), 2.51 (s,3H), 2.38 (m, 2H), 1.98 (m, 2H). MS (ESI+) m/z 304.1 (M+H)⁺.

Example 9

3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)benzamide. Example9 prepared according to the procedure similar to that used for thepreparation of Example 4, substituting 3-carbamoylphenylboronic acid forp-tolylboronic acid, to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 7.96 (s, 1H), 7.69 (d, J=7.63 Hz, 1H), 7.63 (d, J=8.24, 1H),7.51 (t, J=7.78 Hz, 1H), 2.82 (t, J=5.95 Hz, 2H), 2.49 (s, 3H), 2.36 (m,2H), 1.96 (m, 2H). MS (ESI+) m/z 269.1 (M+H)⁻.

Example 10

1-(1H-indol-4-yl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one. Example10 was prepared according to the procedure similar to that used for thepreparation of Example 4, substituting 1H-indol-4-ylboronic acid forp-tolylboronic acid, to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 11.40 (bs, 1H), 7.38 (m, 2H), 7.16 (m, 1H), 6.97 (d, J=6.41Hz, 1H), 6.45 (d, J=3.05 Hz, 1H), 2.65 (t, J=6.10 Hz, 2H), 2.51 (s, 3H),2.37 (m, 2H), 1.91 (m, 2H). MS (ESI+) m/z 265.1 (M+H)⁻.

Example 11

1-(4-methoxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 11 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substituting 4-methoxyphenylboronicacid for p-tolylboronic acid, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 11.45 (bs, 1H), 7.40 (d, J=8.9 Hz, 2H), 7.00 (d, J=8.9Hz, 2H), 3.78 (s, 3H), 2.74 (t, J=5.95 Hz, 2H), 2.46 (s, 3H), 2.34 (m,2H), 1.93 (m, 2H). MS (ESI+) m/z 256.1 (M+H)⁻.

Example 12

1-(3,4-dimethylphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 12 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substituting 3,4-dimethylphenylboronicacid for p-tolylboronic acid, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 11.47 (bs, 1H), 7.26 (s, 1H), 7.18 (m, 2H), 2.77 (t,J=6.10 Hz, 2H), 2.53 (s, 3H), 2.34 (m, 2H), 2.26 (s, 3H), 2.22 (s, 3H),1.93 (m, 2H). MS (ESI+) m/z 254.1 (M+H)⁺.

Example 13

1-(4-chlorophenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 13 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substituting 4-chlorophenylboronicacid for p-tolylboronic acid, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 7.48 (m, 4H), 2.78 (t, J=6.10 Hz, 2H), 2.48 (s, 3H),2.35 (m, 2H), 1.95 (m, 2H). MS (ESI+) m/z 260.1 (M+H)⁺.

Example 14

1-[3-(benzyloxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 14 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substituting2-(3-(benzyloxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane forp-tolylboronic acid, to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 11.56 (bs, 1H), 7.47 (m, 2H), 7.41 (t, J=7.32 Hz, 2H),7.36-7.31 (m, 2H), 7.07 (m, 2H), 6.88 (m, 1H), 5.17 (s, 2H), 2.73 (t,J=5.95 Hz, 2H), 2.46 (s, 3H), 2.34 (m, 2H), 1.93 (m, 2H). MS (ESI+) m/z332.1 (M+H)⁺.

Example 15

1-(2-chlorophenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 15 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substituting 2-chlorophenylboronicacid for p-tolylboronic acid, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 11.49 (bs, 1H), 7.55 (m, 1H), 7.41-7.32 (m, 3H), 2.55(t, J=6.10 Hz, 2H), 2.46 (s, 3H), 2.34 (m, 2H), 1.91 (m, 2H). MS (ESI+)m/z 260.1 (M+H)⁺.

Example 16

1-(1,3-benzodioxol-5-yl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 16 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substitutingbenzo[d][1,3]dioxol-5-ylboronic acid for p-tolylboronic acid, to providethe title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 11.45 (bs, 1H), 7.01 (d,J=1.2 Hz, 1H), 6.98 (d, J=7.9 Hz, 2H), 6.92 (dd, J=1.2, 7.9 Hz, 1H),6.02 (s, 2H), 2.73 (t, J=6.0 Hz, 2H), 2.46 (s, 3H), 2.33 (m, 2H), 1.93(m, 2H). MS (ESI+) m/z 270.1 (M+H)⁺.

Example 17

1-(3,5-dimethylphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 17 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substituting 3,5-dimethylphenylboronicacid for p-tolylboronic acid, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 11.49 (bs, 1H), 7.09 (s, 2H), 6.87 (s, 1H), 2.78 (t,J=6.10 Hz, 2H), 2.47 (s, 3H), 2.34 (m, 2H), 2.30 (s, 6H), 1.94 (m, 2H).MS (ESI+) m/z 254.1 (M+H)⁺.

Example 18

1-[2-(benzyloxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 18 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substituting 2-benzyloxyphenylboronicacid for p-tolylboronic acid, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 11.21 (bs, 1H), 7.43 (m, 2H), 7.37 (m, 2H), 7.32 (d,J=7.02 Hz, 1H), 7.28 (ddd, J=1.68, 5.80, 7.48 Hz, 2H), 7.16 (d, J=7.63Hz, 1H), 7.03 (t, J=7.48 Hz, 1H), 5.13 (s, 2H), 2.56 (t, J=5.95 Hz, 2H),2.44 (s, 3H), 2.29 (m, 2H), 1.85 (m, 2H). MS (ESI+) m/z 332.2 (M+H)⁺.

Example 19

3-methyl-1-(naphthalen-1-yl)-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 19 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substituting 1-naphthylboronic acidfor p-tolylboronic acid, to provide the title compound. ¹H NMR (300 MHz,DMSO-d₆) δ 11.61 (bs, 1H), 7.99 (m, 1H), 7.94 (d, J=8.24 Hz, 1H), 7.83(m, 1H), 7.60-7.54 (m, 3H), 7.47 (m, 1H), 2.51 (s, 3H), 2.45 (t, J=5.95Hz, 2H), 2.38 (m, 2H), 1.92 (m, 2H). MS (ESI+) m/z 278.1 (M+H)⁺.

Example 20

1-(3-methoxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 20 was prepared according to the procedure similar to that usedfor the preparation of Example 4, substituting 3-methoxyphenylboronicacid for p-tolylboronic acid, to provide the title compound. ¹H NMR (300MHz, DMSO-d₆) δ 11.57 (bs, 1H), 7.34 (t, J=7.93 Hz, 1H), 7.06 (m, 1H),7.02 (m, 1H), 6.81 (dd, J=2.29, 7.78 Hz, 1H), 3.79 (s, 3H), 2.79 (t,J=6.10 Hz, 2H), 2.48 (s, 3H), 2.35 (m, 2H), 1.96 (m, 2H). MS (ESI+) m/z256.1 (M+H)⁺.

Example 21

1-(1H-benzimidazol-4-yl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 21 was prepared according to the procedure similar to that usedfor the preparation of Example 1b, substituting1H-benzo[d]imidazol-4-ylboronic acid for phenylboronic acid, to providethe title compound. ¹H NMR (300 MHz, CDCl₃) δ 7.47 (m, 1H), 7.38 (m,2H), 6.91 (s, 1H), 2.98 (m, 2H), 2.66 (s, 3H), 2.53 (m, 2H), 2.10 (m,2H). MS (DCI+) m/z 266.1 (M+H)⁺, 283.3 (M+NH₄)⁺.

Example 22

1-(1H-indol-7-yl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one. Example22 was prepared according to the procedure similar to that used for thepreparation of Example 1b, substituting 1H-indol-7-ylboronic acid forphenylboronic acid, to provide the title compound. ¹H NMR (300 MHz,CDCl₃) δ 8.26 (bs, 1H), 7.64 (d, J=7.54 Hz, 1H), 7.28-7.12(m, 3H), 6.63(m, 1H), 2.67 (m, 2H), 2.64 (s, 3H), 2.52 (m, 2H), 2.03 (m, 2H). MS(DCI+) m/z 265.1 (M+H)⁺, 282.1 (M+NH₄)⁺.

Example 23

3-methyl-1-(2-{[3-(trifluoromethyl)phenoxy]methyl}phenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one.A 10 mL microwave reaction vessel equipped with stir bar was chargedwith example 1a (80 mg, 0.351 mmol),4,4,5,5-tetramethyl-2-({[(3-trifluoromethyl)phenoxy]methyl}phenyl)-1,3,2-dioxaborolane(141 mg, 0.456 mmol), Na₂CO₃ (2M, 1.754 mL, 3.51 mmol) and Pd(Ph₃P)₂Cl₂(14.77 mg, 0.021 mmol) in DME (1.5 mL)/EtOH (1.5 mL) and sealed. Themixture was heated in a Biotage microwave at 120° C. for 30 minutes. Thereaction mixture was diluted with ethyl acetate, washed with water (3×25mL), dried over Na₂SO₄, filtered through sintered glass funnel andconcentrated to give a yellow solid. The sample was transferred insolution onto a 18×150 mm plate. The plate was eluted with 50% ethylacetate/heptane to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ11.33 (s, 1H), 7.60-7.58 (m, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.42-7.39 (m,2H), 7.34-7.32 (m, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.17-7.11 (m, 2H), 5.10(s, 2H), 2.47 (t, J=5.6 Hz, 2H), 2.40 (s, 3H), 2.29 (t, J=5.6 Hz, 2H),1.86 (qui, J=5.6 Hz, 2H). MS (ESI+) m/z 400.2 (M+H)⁺.

Example 24

3-methyl-1-[2-(phenoxymethyl)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 24 was prepared according to the procedure similar to that usedfor the preparation of Example 23, substituting4,4,5,5-tetramethyl-2-(2-(phenoxymethyl)phenyl)-1,3,2-dioxaborolane for4,4,5,5-tetramethyl-2-({[(3-trifluoromethyl)phenoxy]methyl}phenyl)-1,3,2-dioxaborolane,to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ 9.37 (s, 1H),7.50-7.43 (m, 3H), 7.36-7.25 (m, 3H), 7.05-7.00 (m, 3H), 4.90 (s, 2H),2.75 (t, J=6.0 Hz, 2H), 2.47 (t, J=6.0 Hz, 2H), 2.32 (s, 3H), 2.02 (qui,J=6.0 Hz, 2H). MS (ESI+) m/z 331.9 (M+H)⁺.

Example 25

3-methyl-1-{2-[(2-methylphenoxy)methyl]phenyl}-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 25 was prepared according to the procedure similar to that usedfor the preparation of Example 23, substituting4,4,5,5-tetramethyl-2-({[(2-methyl)phenoxy]methyl}phenyl)-1,3,2-dioxaborolanefor4,4,5,5-tetramethyl-2-({[(3-trifluoromethyl)phenoxy]methyl}phenyl)-1,3,2-dioxaborolane,to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ 9.57 (s, 1H),7.49-7.40 (m, 3H), 7.33-7.29 (m, 1H), 7.20-7.15 (m, 2H), 6.96-6.93 (m,2H), 4.93 (s, 2H), 2.75 (t, J=6.0 Hz, 2H), 2.47 (t, J=6.0 Hz, 2H), 2.38(s, 3H), 2.27 (s, 3H), 2.02 (qui, J=6.0 Hz, 2H). MS (ESI+) m/z 346.0(M+H)⁺.

Example 26

2-[2-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)benzyl]-1H-isoindole-1,3(2H)-dione.Example 26 was prepared according to the procedure similar to that usedfor the preparation of Example 23, substituting2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)isoindoline-1,3-dionefor4,4,5,5-tetramethyl-2-({[(3-trifluoromethyl)phenoxy]methyl}phenyl)-1,3,2-dioxaborolane,to provide the title compound. ¹H NMR (400 MHz, CD₃OD) δ 7.97 (d, J=7.6Hz, 1H), 7.62-7.54 (m, 4H), 7.40-7.31 (m, 4H), 4.54 (s, 2H), 2.61 (t,J=6.0 Hz, 2H), 2.56 (s, 3H), 2.47 (t, J=6.0 Hz, 2H), 2.02 (m, 2H). MS(ESI+) m/z 403.2 (M+H₂O+H)⁺.

Example 27

1-[2-(furan-2-yl)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 27 was prepared according to the procedure similar to that usedfor the preparation of Example 23, substituting2-(2-(furan-2-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for4,4,5,5-tetramethyl-2-({[(3-trifluoromethyl)phenoxy]methyl}phenyl)-1,3,2-dioxaborolane,to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (s, 1H),7.78 (d, J=8.0 Hz, 1H), 7.42-7.37(m, 2H), 7.35-7.29 (m, 2H), 6.36 (m,1H), 5.79 (d, J=2.8 Hz, 1H), 2.54 (s, 3H), 2.51 (t, J=6.0 Hz, 2H), 2.45(t, J=6.0 Hz, 2H), 2.00 (m, 2H). MS (ESI+) m/z 292.0 (M+H)⁺.

Example 28

1-(2-hydroxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 28 was prepared according to the procedure similar to that usedfor the preparation of Example 1b, substituting 2-hydroxyphenylboronicacid for phenylboronic acid. Purification by flash chromatography(silica gel, 2-4% methanol in dichloromethane) afforded the titlecompound (39 mg, 32%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.08 (s, 1H) 9.61(s, 1H) 7.19 (dd, J=7.46, 1.70 Hz, 1H) 7.04-7.13 (m, 1H) 6.92 (dd,J=7.97, 1.19 Hz, 1H) 6.79-6.86 (m, 1H) 2.61 (t, J=5.93 Hz, 2H) 2.45 (s,3H) 2.30 (t, J=5.91 Hz, 2H) 1.84-1.95 (m, 2H). MS (ESI+) m/z 242 (M+H)⁺.

Example 29

3-methyl-1-[2-(tetrahydrofuran-3-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one.The product from Example 28 (48.3 mg, 0.20 mmol),(tetrahydrofuran-3-yl)methanol (0.020 mL, 0.210 mmol) andtriphenylphosphine (55.1 mg, 0.210 mmol) were combined intetrahydrofuran (0.1 mL) and sonicated until the solids were dissolved.Diisopropyl azodicarboxylate (0.041 mL, 0.210 mmol) was added andsonication was continued for 2 hours. The reaction mixture waspartitioned with ethyl acetate and water. The organic layer was washedwith brine, dried with anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by flash chromatography (silicagel, 1-2% methanol in dichloromethane) to afford the title compound (13mg, 20%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.03 (s, 1H) 7.22-7.29 (m, 2H)7.09 (d, J=7.93 Hz, 1H) 6.96-7.03 (m, 1H) 3.83-4.03 (m, 2H) 3.48-3.76(m, 4H) 2.55-2.65 (m, 2H) 2.45 (s, 3H) 2.25-2.35 (m, 2H) 1.84-1.94 (m,2H) 1.56-1.70 (m, 1H) 1.14-1.25 (m, 2H). MS (ESI+) m/z 326 (M+H)⁺.

Example 30

1-[2-(cyclopentylmethoxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.The product from Example 28 (48.3 mg, 0.20 mmol),(bromomethyl)cyclopentane (39.1 mg, 0.240 mmol) and potassium carbonate(33.2 mg, 0.240 mmol) were combined in dimethylformamide (1 mL) andheated at 50° C. for 16 hours. The reaction mixture was partitioned withethyl acetate and water. The organic layer was concentrated and theresidue was purified by reverse phase HPLC (C18, 50-95% acetonitrile in10 mM ammonium acetate/water) to afford the title compound (31 mg, 48%).¹H NMR (300 MHz, DMSO-d₆) δ11.01 (s, 1H) 7.20-7.28 (m, 2H) 7.04-7.10 (m,1H) 6.93-7.01 (m, 1H) 3.85 (d, J=6.74 Hz, 2H) 2.59 (t, J=5.95 Hz, 2H)2.43 (s, 3H) 2.23-2.36 (m, 3H) 1.83-1.94 (m, 2H) 1.62-1.76 (m, 2H)1.43-1.60 (m, 4H) 1.24-1.38 (m, 2H). MS (ESI+) m/z 324 (M+H)⁺.

Example 31

3-methyl-1-[2-(tetrahydrofuran-2-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 31 was prepared according to the procedure similar to that usedfor the preparation of Example 30, substituting2-(bromomethyl)tetrahydrofuran for (bromomethyl)cyclopentane, to providethe title compound (24 mg, 37%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.07 (s,1H) 7.19-7.33 (m, 2H) 7.07-7.15 (m, 1H) 6.93-7.06 (m, 1H) 4.16-4.27 (m,1H) 4.06-4.15 (m, 1H) 3.87-3.96 (m, 1H) 3.62-3.83 (m, 2H) 2.65 (t,J=6.15 Hz, 2H) 2.45 (s, 3H) 2.28-2.35 (m, 2H) 1.79-2.01 (m, 5H)1.61-1.73 (m, 1H). MS (HI+) m/z 326 (M+H)⁺.

Example 32

3-methyl-1-[2-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 32 was prepared according to the procedure similar to that usedfor the preparation of Example 30, substituting4-(bromomethyl)tetrahydro-2H-pyran for (bromomethyl)cyclopentane, toprovide the title compound (41 mg, 60%). ¹H NMR (300 MHz, DMSO-d₆) δ11.05 (s, 1H) 7.20-7.29 (m, 2H) 7.03-7.11 (m, 1H) 6.94-7.02 (m, 1H)3.79-3.89 (m, 4H) 3.21-3.30 (m, 2H) 2.58 (t, J=5.95 Hz, 2H) 2.43 (s, 3H)2.26-2.33 (m, 2H) 1.96-2.07 (m, 1H) 1.84-1.94 (m, 2H) 1.55-1.64 (m, 2H)1.17-1.35 (m, 2H). MS (ESI+) m/z 340 (M+H)⁺.

Example 33

3-methyl-1-{2-[2-(morpholin-4-yl)ethoxy]phenyl}-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 33 was prepared according to the procedure similar to that usedfor the preparation of Example 30, substituting4-(2-bromoethyl)morpholine for (bromomethyl)cyclopentane, to provide thetitle compound (46 mg, 65%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.06 (s, 1H)7.17-7.32 (m, 2H) 7.06-7.14 (m, 1H) 6.92-7.04 (m, 1H) 4.13 (t, J=5.59Hz, 2H) 3.51-3.57 (m, 4H) 2.70 (t, J=5.59 Hz, 2H) 2.64 (t, J=6.10 Hz,2H) 2.47 (s, 3H) 2.39-2.44 (m, 4H) 2.28-2.34 (m, 2H) 1.84-1.95 (m, 2H).MS (ESI+) m/z 355 (M+H)⁺.

Example 34

3-methyl-1-[2-(pyridin-2-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 34 was prepared according to the procedure similar to that usedfor the preparation of Example 30, substituting 2-(bromomethyl)pyridinehydrobromide for (bromomethyl)cyclopentane and the reaction wasperformed at room temperature instead of 50° C., to provide the titlecompound (52 mg, 78%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.63 (s, 1H)8.58-8.64 (m, 1H) 7.79-7.90 (m, 1H) 7.48 (d, J=8.14 Hz, 1H) 7.31-7.40(m, 2H) 7.16-7.29 (m, 2H) 6.98-7.07 (m, 1H) 5.28 (s, 2H) 2.66 (t, J=5.93Hz, 2H) 2.49 (s, 3H) 2.28-2.34 (m, 2H) 1.83-1.95 (m, 2H). MS (ESI+) m/z333 (M+H)⁺.

Example 35

3-methyl-1-[2-(quinolin-8-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 35 was prepared according to the procedure similar to that usedfor the preparation of Example 30, substituting 8-(bromomethyl)quinolinefor (bromomethyl)cyclopentane and the reaction was performed at roomtemperature instead of 50° C., to provide the title compound (48 mg,63%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.16 (s, 1H) 8.99 (dd, J=4.24, 1.86Hz, 1H) 8.44 (dd, J=8.48, 1.70 Hz, 1H) 7.98 (dd, J=8.14, 1.36 Hz, 1H)7.85 (dd, J=6.95, 1.19 Hz, 1H) 7.57-7.66 (m, 2H) 7.21-7.34 (m, 3H)6.98-7.07 (m, 1H) 5.78 (s, 2H) 2.57 (t, J=5.93 Hz, 2H) 2.37 (s, 3H)2.20-2.28 (m, 2H) 1.72-1.84 (m, 2H). MS (ESI+) m/z 383 (M+H)⁺.

Example 36

1-[2-(1-benzothiophen-7-ylmethoxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 36 was prepared according to the procedure similar to that usedfor the preparation of Example 30, substituting7-(bromomethyl)benzo[b]thiophene for (bromomethyl)cyclopentane and thereaction was performed at room temperature instead of 50° C., to providethe title compound (39 mg, 50%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.12 (s,1H) 7.86 (dd, J=7.46, 1.36 Hz, 1H) 7.76 (d, J=5.43 Hz, 1H) 7.50 (d,J=5.43 Hz, 1H) 7.35-7.48 (m, 2H) 7.21-7.33 (m, 3H) 6.98-7.08 (m, 1H)5.39 (s, 2H) 2.54 (t, J=5.76 Hz, 2H) 2.40 (s, 3H) 2.21-2.27 (m, 2H)1.75-1.83 (m, 2H). MS (ESI+) m/z 388 (M+H)⁺.

Example 37

3-methyl-1-[2-(pyridin-3-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 37 was prepared according to the procedure similar to that usedfor the preparation of Example 30, substituting 3-(bromomethyl)pyridinehydrobromide for (bromomethyl)cyclopentane and the reaction wasperformed at room temperature instead of 50° C., to provide the titlecompound (8 mg, 12%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.20 (s, 1H) 8.64 (d,J=1.70 Hz, 1H) 8.52 (dd, J=4.75, 1.70 Hz, 1H) 7.74-7.88 (m, 1H) 7.40(dd, J=7.80, 5.09 Hz, 1H) 7.25-7.33 (m, 2H) 7.15-7.21 (m, 1H) 6.95-7.08(m, 1H) 5.17 (s, 2H) 2.54 (t, J=5.76, 2H) 2.43 (s, 3H) 2.23-2.30 (m, 2H)1.76-1.91 (m, 2H). MS (ESI+) m/z 333 (M+H)⁺.

Example 38

1-[2-(1H-indazol-5-ylmethoxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 38 was prepared according to the procedure similar to that usedfor the preparation of Example 30, substituting5-(bromomethyl)-1H-indazole hydrobromide for (bromomethyl)cyclopentaneand the reaction was performed at room temperature instead of 50° C., toprovide the title compound (8 mg, 11%). ¹H NMR (300 MHz, DMSO-d₆) δ13.06 (s, 1H) 11.17 (s, 1H) 8.03 (s, 1H) 7.79 (s, 1H) 7.48-7.56 (m, 1H)7.39-7.46 (m, 1H) 7.17-7.31 (m, 3H) 6.96-7.05 (m, 1H) 5.20 (s, 2H) 2.55(t, J=6.10 Hz, 2H) 2.43 (s, 3H) 2.20-2.27 (m, 2H) 1.75-1.87 (m, 2H). MS(ESI+) m/z 372 (M+H)⁺.

Example 391-(5-amino-2-phenoxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-oneExample 39a

1-(2-fluoro-5-nitrophenyl)-3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one. A250 mL three-necked round-bottomed flask containing Example 1a (2.97 g,13 mmol), 2-fluoro-5-nitrophenylboronic acid (3.61 g, 19.50 mmol),Pd₂(dba)₃ (0.298 g, 0.325 mmol),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamante (0.190 g,0.650 mmol) and potassium phosphate (8.28 g, 39.0 mmol) was purged withnitrogen for 30 minutes. Nitrogen-purged 1,4-dioxane (50 mL) was thentransferred to the three-necked round-bottomed flask and the mixture washeated at 60° C. for 6 hours. The reaction mixture was then cooled toroom temperature and partitioned between ethyl acetate and water. Theorganic layer was washed with brine, dried over anhydrous sodium sulfateand filtered. The filtrate was treated with3-mercaptopropyl-functionalized silica gel, filtered and concentrated.The residue was purified by flash chromatography (silica gel, 0-20%ethyl acetate in dichloromethane) to afford 2.66 g (71%) of the titlecompound.

Example 39b

3-methyl-1-(5-nitro-2-phenoxyphenyl)-6,7-dihydro-2H-isoindol-4(5H)-one.Example 39a (2.65 g, 9.19 mmol), phenol (0.952 g, 10.11 mmol), andCs₂CO₃ (5.99 g, 18.39 mmol) were combined with dimethylformamide (30 mL)and stirred at 50° C. for 1 hour. The reaction mixture was cooled toroom temperature and partitioned between ethyl acetate and water. Theorganic layer was washed with brine twice, dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by flashchromatography (silica gel, 0-20% ethyl acetate in dichloromethane) toafford 3.33 g (100%) of the title compound.

Example 39c

1-(5-amino-2-phenoxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.To a mixture of Example 39b (3.33 g, 9.19 mmol), iron powder (2.57 g,45.9 mmol) and ammonium chloride (1.475 g, 27.6 mmol) was added asolution of tetrahydrofuran (24 mL)/ethanol (24 mL)/water (8 mL). Theresulting mixture was heated under reflux for 9 hours, then cooled toroom temperature and partitioned between ethyl acetate and water. Theorganic layer was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by flashchromatography (silica gel, 20-40% ethyl acetate in dichloromethane) toafford 2.78 g (91%) of the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ11.22 (s, 1H), 7.19 (m, 2H), 6.88 (m, 1H), 6.79 (d, J=8.48 Hz, 1H), 6.72(m, 2H), 6.62 (d, J=2.71 Hz, 1H), 6.54 (dd, J=8.82, 2.71 Hz, 1H), 5.06(s, 2H), 2.56 (t, J=5.93 Hz, 2H), 2.35 (s, 3H), 2.22 (m, 2H), 1.81 (m,2H). MS (ESI+) m/z 333 [M+H]⁻.

Example 40

N-[3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamide.Example 39c (2.78 g, 8.36 mmol), methanesulfonyl chloride (1.564 mL,20.07 mmol) and triethylamine (3.48 mL, 25.09 mmol) were combined indichloromethane (40 mL). The reaction mixture was stirred at roomtemperature for 1 hour and concentrated. The residue was diluted withdioxane (40 mL) and sodium hydroxide (84 mL of 1.0 M aqueous solution,84 mmol) and heated at 50° C. for 1 hour. The reaction mixture waspartitioned with ethyl acetate and saturated aqueous ammonium chloridesolution. The organic layer was washed with brine, dried with anhydroussodium sulfate, filtered and concentrated. The residue was purified byflash chromatography (silica gel, 1-2% methanol in dichloromethane)followed by trituration (dichloromethane) to afford the title compound(3.05 g, 89%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.35 (s, 1H) 9.71 (s, 1H)7.25-7.34 (m, 3H) 7.10-7.16 (m, 1H) 7.00-7.07 (m, 1H) 6.97 (d, J=8.82Hz, 1H) 6.86-6.92 (m, 2H) 3.02 (s, 3H) 2.60 (t, J=5.93 Hz, 2H) 2.41 (s,3H) 2.27 (t, J=6.10 Hz, 2H) 1.80-1.93 (m, 2H). MS (ESI+) m/z 411 (M+H)⁺.

Example 41N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamide

Example 41a

2,3-dimethyl-1-(5-nitro-2-phenoxyphenyl)-6,7-dihydro-2H-isoindol-4(5H)-one.Example 39b (127 mg, 0.350 mmol) in tetrahydrofuran (2 mL) was treatedwith 60% sodium hydride (15.42 mg, 0.386 mmol), stirred at roomtemperature for 1 hour, treated with iodomethane (0.024 mL, 0.386 mmol)and stirred at room temperature for 2 hours. The reaction mixture waspartitioned with ethyl acetate and water. The organic layer was washedwith brine, dried with anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by flash chromatography (silicagel, 0-2% methanol in dichloromethane) to afford the title compound (105mg, 80%).

Example 41b

1-(5-amino-2-phenoxyphenyl)-2,3-dimethyl-6,7-dihydro-2H-isoindol-4(5H)-one.Example 41b was prepared according to the procedure similar to that usedfor the preparation of Example 39c, substituting Example 41a for Example39b, to provide the title compound (90 mg, 95%).

Example 41c

N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamide.Example 41c was prepared according to the procedure similar to that usedfor the preparation of Example 40, substituting Example 41b for Example39c. Purification by flash chromatography (silica gel, 2% methanol indichloromethane) afforded the title compound (43 mg, 84%). ¹H NMR (300MHz, DMSO-d₆) δ 9.75 (s, 1H) 7.19-7.29 (m, 3H) 7.16 (d, J=2.78 Hz, 1H)7.07 (d, J=8.73 Hz, 1H) 7.00 (t, J=7.34 Hz, 1H) 6.81 (d, J=7.54 Hz, 2H)3.33 (s, 3H) 3.02 (s, 3H) 2.44 (s, 3H) 2.18-2.37 (m, 4H) 1.66-1.90 (m,2H). MS (ESI+) m/z 425 (M+H)⁺.

Example 42

N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]acetamide.Example 41b (41.6 mg, 0.12 mmol) in acetic anhydride (0.5 mL, 5.30 mmol)was heated in microwave at 100° C. for 30 minutes. The reaction mixturewas concentrated and the residue was purified by flash chromatography(silica gel, 1-2% methanol in dichloromethane) to afford the titlecompound (38 mg, 82%). ¹H NMR (300 MHz, DMSO-d₆) δ 10.04 (s, 1H)7.51-7.67 (m, 2H) 7.16-7.30 (m, 2H) 6.93-7.08 (m, 2H) 6.74-6.80 (m, 2H)3.30 (s, 3H) 2.43 (s, 3H) 2.12-2.35 (m, 4H) 2.05 (s, 3H) 1.77-1.88 (m,1H) 1.66-1.76 (m, 1H). MS (ESI+) m/z 389 (M+H)⁻.

Example 431-[5-amino-2-(phenylsulfanyl)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-oneExample 43a

3-methyl-1-(5-nitro-2-(phenylthio)phenyl)-6,7-dihydro-2H-isoindol-4(5H)-one.Example 39a (58 mg, 0.201 mmol) and sodium thiophenoxide (29.2 mg, 0.221mmol) were combined in dimethylformamide (2 mL) and heated at 50° C. for2 hours. The reaction mixture was partitioned with ethyl acetate andwater. The organic layer was washed with brine twice, dried withanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by flash chromatography (silica gel, 0-1% methanol indichloromethane) to afford the title compound (46 mg, 60%).

Example 43b

1-[5-amino-2-(phenylsulfanyl)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 43b was prepared according to the procedure similar to that usedfor the preparation of Example 39c, substituting Example 43a for Example39b. Purification by flash chromatography (silica gel, 2% methanol indichloromethane) afforded the title compound (35 mg. 84%). ¹H NMR (300MHz, DMSO-d₆) δ 11.25 (s, 1H) 7.10-7.24 (m, 3H) 6.98-7.06 (m, 1H)6.81-6.88 (m, 2H) 6.54-6.61 (m, 2H) 5.53 (s, 2H) 2.41 (t, J=5.93 Hz, 2H)2.37 (s, 3H) 2.19-2.26 (m, 2H) 1.73-1.83 (m, 2H). MS (ESI+) m/z 349(M+H)⁺.

Example 44

N-[3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-(phenylsulfanyl)phenyl]methanesulfonamide.Example 44 was prepared according to the procedure similar to that usedfor the preparation of Example 40, substituting Example 43b for Example39c. Purification by flash chromatography (silica gel, 2% methanol indichloromethane) afforded the title compound (33 mg, 84%). ¹H NMR (300MHz, DMSO-d₆) δ 11.40 (s, 1H) 9.96 (s, 1H) 7.18-7.31 (m, 4H) 7.08-7.16(m, 4H) 3.06 (s, 3H) 2.41-2.48 (m, 5H) 2.23-2.31 (m, 2H) 1.80-1.87 (m,2H). MS (ESI+) m/z 427 (M+H)⁺.

Example 451-[5-amino-2-(2,4-difluorophenoxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-oneExample 45a

1-(2-(2,4-difluorophenoxy)-5-nitrophenyl)-3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one.Example 45a prepared according to the procedure similar to that used forthe preparation of Example 39b, substituting 2,4-difluorophenol forphenol, to provide the title compound (1.01 g, 73%).

Example 45b

1-[5-amino-2-(2,4-difluorophenoxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 45b was prepared according to the procedure similar to that usedfor the preparation of Example 39c, substituting Example 45a for Example39b, to provide the title compound (805 mg, 87%). ¹H NMR (300 MHz,DMSO-d₆) δ 11.24 (s, 1H) 7.22-7.33 (m, 1H) 6.83-6.94 (m, 1H) 6.64-6.77(m, 2H) 6.60 (d, J=2.71 Hz, 1H) 6.49-6.56 (m, 1H) 5.07 (s, 2H) 2.54 (t,J=5.76 Hz, 2H) 2.37 (s, 3H) 2.24 (t, J=5.76 Hz, 2H) 1.76-1.87 (m, 2H).MS (ESI+) m/z 369 (M+H)⁺.

Example 46

N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]methanesulfonamide.Example 46 was prepared according to the procedure similar to that usedfor the preparation of Example 40, substituting Example 45b for Example39c. Purification by flash chromatography (silica gel, 1-2% methanol indichloromethane) afforded the title compound (49 mg, 81%). ¹H NMR (300MHz, DMSO-d₆) δ 11.36 (s, 1H) 9.68 (s, 1H) 7.34-7.47 (m, 1H) 7.25 (d,J=2.71 Hz, 1H) 6.99-7.16 (m, 3H) 6.83 (d, J=8.48 Hz, 1H) 3.01 (s, 3H)2.60 (t, J=5.93 Hz, 2H) 2.44 (s, 3H) 2.25-2.33 (m, 2H) 1.79-1.93 (m,2H). MS (ESI+) m/z 447 (M+H)⁺.

Example 47

N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]ethanesulfonamide.Example 47 was prepared according to the procedure similar to that usedfor the preparation of Example 40, substituting Example 45b for Example39c, and ethanesulfonyl chloride for methanesulfonyl chloride,respectively. Purification by flash chromatography (silica gel, 1-2%methanol in dichloromethane) afforded the title compound (53 mg, 85%).¹H NMR (300 MHz, DMSO-d₆) δ 11.35 (s, 1H) 9.75 (s, 1H) 7.34-7.48 (m, 1H)7.25 (d, J=2.37 Hz, 1H) 6.96-7.16 (m, 3H) 6.82 (d, J=8.82 Hz, 1H) 3.10(q, J=7.23 Hz, 2H) 2.59 (t, J=5.93 Hz, 2H) 2.44 (s, 3H) 2.24-2.33 (m,2H) 1.80-1.92 (m, 2H) 1.22 (t, J=7.29 Hz, 3H). MS (ESI+) m/z 461 (M+H)⁺.

Example 48

N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]-2,2,2-trifluoroethanesulfonamide.Example 45b (50 mg, 0.136 mmol), 2,2,2-trifluoroethanesulfonyl chloride(29.7 mg, 0.163 mmol), and triethylamine (0.057 mL, 0.407 mmol) werecombined in dichloromethane (2 mL). The reaction mixture was stirred atroom temperature for 2 hours, concentrated, and the residue waspartitioned with ethyl acetate and water. The organic layer was washedwith brine, dried with anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by flash chromatography (silicagel, 1-2% methanol in dichloromethane) to afford the title compound (18mg, 26%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.35 (s, 1H) 10.40 (s, 1H)7.35-7.49 (m, 1H) 7.26 (d, J=2.71 Hz, 1H) 7.00-7.18 (m, 3H) 6.83 (d,J=8.82 Hz, 1H) 4.53 (q, J=9.83 Hz, 2H) 2.60 (t, J=5.93 Hz, 2H) 2.45 (s,3H) 2.25-2.34 (m, 2H) 1.81-1.94 (m, 2H). MS (ESI+) m/z 515 (M+H)⁺.

Example 49

N′-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]-N,N-dimethylsulfuricdiamide. Example 45b (50 mg, 0.136 mmol), dimethylsulfamoyl chloride(0.017 mL, 0.163 mmol), and cesium carbonate (66.3 mg, 0.204 mmol) werecombined in dimethylformamide (1 mL) and the reaction mixture was heatedby microwave at 80° C. for 1 hour. Dimethylsulfamoyl chloride (0.017 mL,0.163 mmol) was added again and the reaction mixture was heated bymicrowave at 80° C. for another 1 hour. The reaction mixture waspartitioned with ethyl acetate and water. The organic layer was washedwith brine twice, dried with anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by flash chromatography (silicagel, 1-2% methanol in dichloromethane) to afford the title compound (14mg, 22%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.33 (s, 1H) 9.87 (s, 1H)7.32-7.50 (m, 1H) 7.23 (d, J=2.78 Hz, 1H) 6.94-7.18 (m, 3H) 6.81 (d,J=8.73 Hz, 1H) 2.71 (s, 6H) 2.59 (t, J=5.95 Hz, 2H) 2.43 (s, 3H)2.25-2.32 (m, 2H) 1.82-1.92 (m, 2H). MS (ESI+) m/z 476 (M+H)⁺.

Example 50

N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]acetamide.Example 50 was prepared according to the procedure similar to that usedfor the preparation of Example 42, substituting Example 45b for Example41b, to afford the title compound (35 mg, 63%). ¹H NMR (300 MHz,DMSO-d₆) δ 11.33 (s, 1H) 9.98 (s, 1H) 7.68 (d, J=2.71 Hz, 1H) 7.28-7.49(m, 2H) 6.92-7.12 (m, 2H) 6.82 (d, J=8.82 Hz, 1H) 2.59 (t, J=5.76 Hz,2H) 2.42 (s, 3H) 2.24-2.32 (m, 2H) 2.04 (s, 3H) 1.81-1.92 (m, 2H). MS(ESI+) m/z 411 (M+H)⁺.

Example 51

N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]-1H-pyrrole-2-carboxamide.1H-pyrrole-2-carboxylic acid (18.10 mg, 0.163 mmol) in tetrahydrofuran(2 mL) was treated with oxalyl dichloride (0.024 mL, 0.271 mmol) and onedrop of dimethylformamide. The reaction mixture was stirred at roomtemperature for 30 minutes and concentrated. The residue was azeotropedwith toluene and dissolved in tetrahydrofuran (2 mL). Example 45b (50mg, 0.136 mmol) and triethylamine (0.076 mL, 0.543 mmol) were added andthe reaction mixture was stirred at room temperature for 30 minutes. Thereaction mixture was partitioned with ethyl acetate and water. Theorganic layer was washed with brine, dried with anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by flashchromatography (silica gel, 1-2% methanol in dichloromethane) to affordthe title compound (40 mg, 64%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.66 (s,1H) 11.36 (s, 1H) 9.80 (s, 1H) 7.88 (d, J=2.38 Hz, 1H) 7.60 (dd, J=8.93,2.58 Hz, 1H) 7.32-7.46 (m, 1H) 7.02-7.08 (m, 3H) 6.93-6.98 (m, 1H) 6.86(d, J=8.73 Hz, 1H) 6.13-6.20 (m, 1H) 2.64 (t, J=5.95 Hz, 2H) 2.43 (s,3H) 2.24-2.34 (m, 2H) 1.82-1.94 (m, 2H). MS (ESI+) m/z 462 (M+H)⁺.

Example 52N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl}ethanesulfonamideExample 52a

1-(2-(4,4-difluorocyclohexyloxy)-5-nitrophenyl)-3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one.To 4,4-difluorocyclohexanol (102 mg, 0.75 mmol) in tetrahydrofuran (2mL) was added 60% sodium hydride (36 mg, 0.90 mmol) under nitrogen andthe reaction mixture was stirred at room temperature for 1 hour. Example39a (43.2 mg, 0.15 mmol) was added and the reaction mixture was heatedat 50° C. under nitrogen for 2 hours. The reaction mixture waspartitioned with ethyl acetate and 1M HCl. The organic layer was washedwith brine, dried with anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by flash chromatography (silicagel, 5-20% ethyl acetate in dichloromethane), followed by trituration(10% dichloromethane in hexane) to afford the title compound (32 mg,53%).

Example 52b

1-(5-amino-2-(4,4-difluorocyclohexyloxy)phenyl)-3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one.Example 52a (58 mg, 0.143 mmol) and 10% palladium on carbon (30.5 mg,0.029 mmol) were combined in ethyl acetate (20 mL). The reaction mixturewas hydrogenated under a hydrogen balloon atmosphere for 3 hours,filtered and the filtrate was concentrated to afford the title compound(49 mg, 91%).

Example 52c

N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl}ethanesulfonamide.Example 52c was prepared according to the procedure similar to that usedfor the preparation of Example 40, substituting Example 52b for Example39c, and ethanesulfonyl chloride for methanesulfonyl chloride,respectively. Purification by flash chromatography (silica gel, 1-2%methanol in dichloromethane) and trituration (20% dichloromethane inhexane) afforded the title compound (44 mg, 77%). ¹H NMR (300 MHz,DMSO-d₆) δ 11.16 (s, 1H) 9.57 (s, 1H) 7.05-7.22 (m, 3H) 4.38-4.51 (m,1H) 3.04 (q, J=7.54 Hz, 2H) 2.57 (t, J=5 .7 5 Hz, 2H) 2.44 (s, 3H)2.29-2.36 (m, 2H) 1.71-1.92 (m, 10H) 1.21 (t, J=7.34 Hz, 3H). MS (ESI+)m/z 467 (M+H)⁺.

Example 53 methyl3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxybenzoateExample 53a

methyl4-fluoro-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)benzoate.Example 53a prepared according to the procedure similar to that used forthe preparation of Example 39a, substituting(2-fluoro-5-methoxycarbonylphenyl)boronic acid for2-fluoro-5-nitrophenylboronic acid. Purification by flash chromatography(silica gel, 0-60% ethyl acetate in hexane) afforded the title compound(3.8 g, 72%).

Example 53b

methyl3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxybenzoate.Example 53b was prepared according to the procedure similar to that usedfor the preparation of Example 39b, substituting Example 53a for Example39a and the reaction was performed at 120° C. instead of 50° C., toprovide the title compound (451 mg, 60%). ¹H NMR (300 MHz, DMSO-d₆) δ11.50 (s, 1H) 7.99 (d, J=2.03 Hz, 1H) 7.84 (dd, J=8.65, 2.20 Hz, 1H)7.38-7.48 (m, 2H) 7.17-7.25 (m, 1H) 7.08-7.15 (m, 2H) 6.89 (d, J=8.48Hz, 1H) 3.85 (s, 3H) 2.62 (t, J=5.93 Hz, 2H) 2.46 (s, 3H) 2.25-2.33 (m,2H) 1.83-1.93 (m, 2H). MS (ESI+) m/z 376 (M+H)⁺.

Example 54

3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxybenzoicacid. A mixture of Example 53b (410 mg, 1.092 mmol) and sodium hydroxide(3.28 mL of 1.0 M aqueous solution, 3.28 mmol) in tetrahydrofuran (10mL) and water (5 mL) was heated at reflux for 2 hours. The reactionmixture was partitioned with ethyl acetate and water. The aqueous layerwas acidified to pH 1 with 1M HCl, extracted with ethyl acetate, driedwith anhydrous sodium sulfate, filtered and concentrated to provide thetitle compound (385 mg, 98%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.83 (s, 1H)11.47 (s, 1H) 7.98 (d, J=2.03 Hz, 1H) 7.82 (dd, J=8.48, 2.37 Hz, 1H)7.38-7.48 (m, 2H) 7.16-7.23 (m, 1H) 7.06-7.12 (m, 2H) 6.88 (d, J=8.82Hz, 1H) 2.62 (t, J=5.93 Hz, 2H) 2.45 (s, 3H) 2.26-2.31 (m, 2H) 1.84-1.92(m, 2H). MS (ESI+) m/z 362 (M+H)⁺.

Example 55

N-ethyl-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxybenzamide.Example 54 (36.1 mg, 0.10 mmol), HATU (76 mg, 0.200 mmol), andN,N-diisopropylethylamine (0.035 mL, 0.200 mmol) were combined intetrahydrofuran (2 mL), stirred at room temperature for 5 minutes,treated with ethanamine (0.1 mL of 2.0 M solution in tetrahydrofuran,0.20 mmol) and stirred at room temperature for 1 hour. The reactionmixture was partitioned with ethyl acetate and 1M HCl. The organic layerwas washed with brine, dried with anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by flash chromatography (silicagel, 1-2% methanol in dichloromethane), followed by trituration(methanol) to afford the title compound (19 mg, 49%). ¹H NMR (300 MHz,DMSO-d₆) δ 11.44 (s, 1H) 8.42 (t, J=5.43 Hz, 1H) 7.92 (d, J=2.03 Hz, 1H)7.75 (dd, J=8.65, 2.20 Hz, 1H) 7.33-7.43 (m, 2H) 7.10-7.18 (m, 1H)6.98-7.06 (m, 2H) 6.90 (d, J=8.48 Hz, 1H) 3.24-3.32 (m, 2H) 2.60 (t,J=6.10 Hz, 2H) 2.44 (s, 3H) 2.25-2.32 (m, 2H) 1.80-1.92 (m, 2H) 1.12 (t,J=7.12 Hz, 3H). MS (ESI+) m/z 389 (M+H)⁺.

Example 56

3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxy-N-(tetrahydrofuran-2-ylmethyl)benzamide.Example 56 prepared according to the procedure similar to that used forthe preparation of Example 55, substituting(tetrahydrofuran-2-yl)methanamine for ethanamine and reaction mixturewas stirred for 24 hours instead of 1 hour. Purification by flashchromatography (silica gel, 1-2% methanol in dichloromethane) followedby trituration (50% dichloromethane in hexane) afforded the titlecompound (29 mg, 65%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.44 (s, 1H) 8.48(t, J=5.76 Hz, 1H) 7.94 (d, J=2.03 Hz, 1H) 7.76 (dd, J=8.48, 2.37 Hz,1H) 7.30-7.48 (m, 2H) 7.11-7.20 (m, 1H) 6.99-7.08 (m, 2H) 6.90 (d,J=8.82 Hz, 1H) 3.90-4.04 (m, 1H) 3.72-3.82 (m, 1H) 3.57-3.67 (m, 1H)3.30-3.36 (m, 2H) 2.60 (t, J=5.93 Hz, 2H) 2.44 (s, 3H) 2.28 (t, J=6.10Hz, 2H) 1.74-1.97 (m, 5H) 1.53-1.63 (m, 1H). MS (ESI+) m/z 445 (M+H)⁺.

Example 57

3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxy-N-(1,3-thiazol-2-yl)benzamide.Example 57 was prepared according to the procedure similar to that usedfor the preparation of Example 55, substituting thiazol-2-amine forethanamine and the reaction mixture was stirred for 24 hours instead of1 hour, to provide the title compound (11 mg, 25%). ¹H NMR (300 MHz,DMSO-d₆) δ 12.55 (s, 1H) 11.44 (s, 1H) 8.20 (d, J=2.38 Hz, 1H) 8.02 (dd,J=8.53, 2.18 Hz, 1H) 7.56 (d, J=3.57 Hz, 1H) 7.39-7.50 (m, 2H) 7.27 (d,J=3.57 Hz, 1H) 7.16-7.25 (m, 1H) 7.07-7.15 (m, 2H) 6.91 (d, J=8.73 Hz,1H) 2.66 (t, J=5.95 Hz, 2H) 2.47 (s, 3H) 2.23-2.36 (m, 2H) 1.84-1.94 (m,2H). MS (ESI+) m/z 444 (M+H)⁺.

Example 581-(1,3-benzodioxol-5-yl)-3,6,6-trimethyl-2,5,6,7-tetrahydro-4H-isoindol-4-oneExample 58a

ethyl3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylate. A25 mL roundbottom flask with stirbar was charged with2-acetyl-5,5-dimethylcyclohexane-1,3-dione (5 g, 27.4 mmol) and sodiumacetate (2.57 g, 31.3 mmol) in acetic acid (30 mL). The well-stirredmixture was placed in a 100° C. oil bath and became homogeneous. Asolution of diethyl 2-aminomalonate (4.184 g, 23.88 mmol) in 10 mLacetic acid was added dropwise, and the mixture was stirred at 100° C.After 3 hours an additional portion of sodium acetate (2.75 g, 33.5mmol) was added. After 20 hours, the mixture was poured over ice, thenshaken in a separatory funnel with water and ether (250 mL). Theorganics were washed twice with aqueous sodium bicarbonate then driedover anhydrous sodium sulfate. Filtration and solvent removal gave abrown solid. The crude material was adsorbed on silica gel andchromatographed on a 220 g silica gel cartridge eluting with 10-100%ethyl acetate/hexanes to provide the title compound.

Example 58b

3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid.A 200 mL recovery flask with stirbar was charged with Example 58a (1.184g, 4.75 mmol) and lithium hydroxide monohydrate (0.57 g, 13.58 mmol) intetrahydrofuran (40.0 mL) and water (20 mL). The mixture was stirred ina 60° C. oil bath for 56 hours. The mixture was allowed to cool, thendiluted with 80 mL water and extracted twice with ether. The aqueousphase was acidified with conc. HCl and extracted with dichloromethaneand ethyl acetate sequentially. These organic extracts were combined anddried over anhydrous sodium sulfate. Filtration and solvent removalprovided the title compound.

Example 58c

3,6,6-trimethyl-6,7-dihydro-2H-isoindol-4(5H)-one. A 250 mL recoveryflask with stirbar was charged with Example 58b (0.61 g, 2.76 mmol) inethanol (25.00 mL)/water (1 mL). The flask was placed in a 100° C. oilbath and treated with concentrated HCl (2.8 mL, 28.0 mmol). The mixturewas heated for 30 minutes, then allowed to cool. The solution wasreduced to about ⅓ volume by rotovap then shaken in a separatory funnelwith 100 mL each water and dichloromethane. The organics were washedwith aqueous sodium bicarbonate and water, and dried over anhydroussodium sulfate. Filtration and solvent removal provided the titlecompound.

Example 58d

1-bromo-3,6,6-trimethyl-6,7-dihydro-2H-isoindol-4(5H)-one. A 50 mLroundbottom flask with stirbar was charged with Example 58c (0.395 g,2.229 mmol) in tetrahydrofuran (6 mL) and cooled to −78° C. undernitrogen. Recrystallized N-bromo succinimide (0.402 g, 2.259 mmol) wasadded and the mixture stirred for 30 minutes. The reaction mixture waspoured into a separatory funnel containing aqueous sodium sulfite andextracted into 60 mL ether. The organics were washed with aqueous sodiumbicarbonate and dried over magnesium sulfate. After filtration andsolvent removal, the crude material was adsorbed on silica gel andchromatographed on a 40 g silica cartridge eluting with 10-100% ethylacetate/hexanes to provide the title compound.

Example 58e

1-(1,3-benzodioxol-5-yl)-3,6,6-trimethyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.A 4 mL vial was charged with a stir bar, a solution of example 58d(14.09 mg, 0.055 mmol) in ethanol (500 μL, a solution ofbenzo[d][1,3]dioxol-5-ylboronic acid (10.95 mg, 1.2 eq, 0.066 mmol) inethanol (220.04 μL), an aqueous solution of 1M Cs₂CO₃ (110.02 μL, 2.0equivalents, 0.11 mmol), and SiliaCat DPP-Pd resin (Silicycle, Inc.)(20.37 mg, 0.10 equivalent, 0.27 mmol/g loading), capped and placed inAnton Paar Synthos 3000 parallel microwave optimizer at 120° C. for 30minutes. Upon completion the crude material was filtered, dried, and theresidue was purified by reverse phase HPLC (C 18, 0-100% CH₃CN/water(0.1% TFA)) to afford the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ7.01 (d, J=1.5 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.93 (dd, J=1.5, 8.3 Hz,1H), 6.02 (s, 2H), 2.62 (s, 2H), 2.46 (s, 3H), 2.21 (s, 2H), 0.98 (s,6H). MS (ESI+) m/z 298.1 (M+H)⁻.

Example 59

3,6,6-trimethyl-1-phenyl-2,5,6,7-tetrahydro-4H-isoindol-4-one. Example59 was prepared according to the procedure similar to that used for thepreparation of Example 58e, substituting phenylboronic acid forbenzo[d][1,3]dioxol-5-ylboronic acid, to provide the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ 7.48-7.41 (m, 4H), 7.07 (t, J=7.17 Hz, 1H),2.69 (s, 2H), 2.48 (s, 3H), 2.23 (s, 2H), 0.99 (s, 6H). MS (ESI+) m/z254.1 (M+H)⁺.

Example 60

1-(2,5-dimethylphenyl)-3,6,6-trimethyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 60 was prepared according to the procedure similar to that usedfor the preparation of Example 58e, substituting2,5-dimethylphenylboronic acid for benzo[d][1,3]dioxol-5-ylboronic acid,to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 7.18 (d,J=7.63 Hz, 1H), 7.07 (d, J=7.63 Hz, 1H), 7.01 (s, 1H), 2.44 (s, 3H),2.31 (s, 2H), 2.28 (s, 3H), 2.20 (s, 2H), 2.17 (s, 3H), 0.95 (s, 6H). MS(ESI+) m/z 282.1 (M+H)⁺.

Example 61

3,6,6-trimethyl-1-[2-(morpholin-4-yl)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 61 was prepared according to the procedure similar to that usedfor the preparation of Example 58e, substituting2-morpholinophenylboronic acid for benzo[d][1,3]dioxol-5-ylboronic acid,to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 7.27 (m, 1H),7.19 (dd, J=1.68, 7.78 Hz, 1H), 7.06 (m, 2H), 3.61 (m, 4H), 2.71 (m,4H), 2.53 (s, 2H), 2.48 (s, 3H), 2.21 (s, 2H), 0.96 (s, 6H). MS (ESI+)m/z 339.1 (M+H)⁻.

Example 62

1-[2-(benzyloxy)phenyl]-3,6,6-trimethyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 62 was prepared according to the procedure similar to that usedfor the preparation of Example 58e, substituting2-benzyloxyphenylboronic acid for benzo[d][1,3]dioxol-5-ylboronic acid,to provide the title compound. ¹H NMR (300 MHz, DMSO-d₆) δ 7.42 (m, 2H),7.39-7.27 (m, 5H), 7.17 (d, J=7.7 Hz, 1H), 7.03 (t, J=7.5 Hz, 1H), 5.12(s, 2H), 2.44 (s, 3H), 2.42 (s, 2H), 2.13 (s, 2H), 0.89 (s, 6H). MS(ESI+) m/z 360.1 (M+H)⁺.

Example 63

3,6,6-trimethyl-1-(2-phenoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 63 was prepared according to the procedure similar to that usedfor the preparation of Example 58e, substituting 2-phenoxyphenylboronicacid for benzo [d][1,3]dioxol-5-ylboronic acid, to provide the titlecompound. ¹H NMR (300 MHz, DMSO-d₆) δ 7.41 (dd, J=1.8, 7.6 Hz, 1H),7.34-7.24 (m, 4H), 7.01 (m, 2H), 6.85 (d, J=7.9 Hz, 2H), 2.47 (s, 2H),2.40 (s, 3H), 2.14 (s, 2H), 0.88 (s, 6H). MS (ESI+) m/z 346.1 (M+H)⁺.

Example 64

N-[3-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]methanesulfonamide.Example 64 was prepared according to the procedure similar to that usedfor the preparation of Example 58e, substituting3-(methylsulfonamido)phenylboronic acid forbenzo[d][1,3]dioxol-5-ylboronic acid, to provide the title compound. ¹HNMR (300 MHz, DMSO-d₆) δ 7.38 (t, J=7.78 Hz, 1H), 7.30 (m, 1H), 7.23 (m,1H), 7.07 (m, 1H), 3.01 (s, 3H), 2.66 (s, 2H), 2.48 (s, 3H), 2.24 (s,2H), 0.99 (s, 6H). MS (ESI+) m/z 347.1 (M+H)⁺.

Example 653,6-dimethyl-1-(2-phenoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-oneExample 65a

ethyl 3,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylate.A 50 mL round bottom flask with stirbar was charged with2-acetyl-5-methylcyclohexane-1,3-dione (2.019 g, 12.00 mmol) and sodiumacetate (3.87 g, 47.2 mmol) in acetic acid (15 mL). The well-stirredmixture was placed in a 100° C. oil bath and became homogeneous. Asolution of diethyl 2-aminomalonate, hydrochloric acid (2.79 g, 13.18mmol) in acetic acid (10.00 mL) was added dropwise, and the mixture wasstirred at 100° C. After 18 hours, the mixture was poured over ice, thenshaken in a reparatory funnel with water and ether (250 mL). Theorganics were washed twice with aqueous sodium hydroxide (pH of secondwash was basic) then dried over anhydrous sodium sulfate. Afterfiltration and solvent removal, the crude material was adsorbed onsilica gel and chromatographed on a 150 g silica gel cartridge elutingwith 10-100% ethyl acetate/hexanes to provide the title compound.

Example 65b

3,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid. A100 mL recovery flask with stirbar was charged with Example 65a (0.879g, 3.74 mmol) and lithium hydroxide monohydrate (0.345 g, 8.22 mmol) intetrahydrofuran (30.0 mL) and water (15 mL). The mixture was stirred ina 60° C. oil bath over three days. LCMS trace shows clean conversion toa peak with the expected mass. The mixture was diluted with 40 mL water,acidified with concentrated HCl, and allowed to cool with vigorousstirring. After chilling in an ice bath, the suspension was filtered.The precipitate was vacuum dried to provide the title compound.

Example 65c

3,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindole-1-carboxylic acid. A100 mL round-bottom flask with stirbar and reflux condenser was chargedwith Example 65b (0.648 g, 3.13 mmol) in ethanol (30.0 mL)/water (1.2mL). The flask was placed in a 100° C. oil bath and treated withconcentrated HCl (2.5 mL, 30.4 mmol). The mixture was heated for 30minutes, then allowed to cool. The solution was shaken in a separatoryfunnel with 100 mL each of brine and dichloromethane. The organics werewashed with aqueous sodium bicarbonate, and dried over anhydrous sodiumsulfate. Filtration and solvent removal gave the title compound.

Example 65d

1-bromo-3,6-dimethyl-6,7-dihydro-2H-isoindol-4(5H)-one. A 50 mL roundbottom flask with stirbar was charged with Example 65c (.434 g, 2.66mmol) in tetrahydrofuran (10 mL) and cooled to −78° C. under nitrogen.Recrystallized N-bromo succinimide (0.529 g, 2.97 mmol) was added andthe mixture stirred for 30 minutes. The reaction mixture was poured intoa separatory funnel containing aqueous sodium sulfite and extracted into75 mL ether. The organics were washed with aqueous sodium bicarbonateand dried over magnesium sulfate. Filtration and solvent removalprovided 0.632 g lavender solid which was chromatographed on a 40 gsilica cartridge eluting with 10-100% ethyl acetate/hexanes to providethe title compound.

Example 65e

3,6-dimethyl-1-(2-phenoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one. A5 mL microwave reaction vessel equipped with stirbar was charged withExample 65d (0.078 g, 0.322 mmol), 2-phenoxyphenylboronic acid (0.106 g,0.495 mmol), 2 M aqueous sodium carbonate (1.6 mL, 3.20 mmol) andbis(triphenylphosphine)palladium(II) dichloride (0.015 g, 0.021 mmol) inethanol (1.4 mL)/DME (1.4 mL) and sealed. The mixture was heated at 120°C. for 30 minutes in a Biotage Initiator 2 monomode microwave reactor,then cooled to ambient temperature. The mixture was shaken in aseparatory funnel with 50 mL ethyl acetate and 50 mL brine. The organicswere dried over anhydrous sodium sulfate. After filtration and solventremoval the residue was purified by reverse phase HPLC (C18, 0-100%CH₃CN/water (0.1% TFA)) to afford the title compound. ¹H NMR (300 MHz,CDCl₃) δ 9.15 (bs, 1H), 7.51 (m, 1H), 7.35 (m, 2H), 7.19 (m, 3H), 7.01(d, J=2.7 Hz, 2H), 6.93 (m, 1H), 2.98 (m, 1H), 2.54 (s, 3H), 2.53 (m,2H), 2.26 (m, 2H), 1.13 (d, J=3.2 Hz, 3H). MS (ESI+) m/z 332.2 (M+H)⁺.

Example 66

1-(5-amino-2-phenoxyphenyl)-3,6-dimethyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 66 was prepared according to the procedure similar to that usedfor the preparation of Example 65e, substituting4-phenoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for2-phenoxyphenylboronic acid, to provide the title compound. ¹H NMR (300MHz, CDCl₃) δ 9.07 (bs, 1H), 7.32 (m, 2H), 7.04 (t, J=7.6 Hz, 1H),6.92-6.83 (m, 3H), 6.59 (dd, J=3.1, 9.2 Hz, 1H), 2.96 (m, 1H), 2.49 (s,3H), 2.48 (m, 2H), 2.24 (m, 2H), 1.11 (d, J=6.1 Hz, 3H). MS (ESI+) m/z347.2 (M+H)⁺.

Example 67

N-[3-(3,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamide.Example 66 (0.074 g, 0.213 mmol) in tetrahydrofuran (4 mL) was treatedsequentially with methanesulfonyl chloride (0.041 mL, 0.533 mmol) andtriethylamine (0.089 mL, 0.639 mmol) and stirred at ambient temperature.After 90 minutes of stirring, aqueous sodium hydroxide (1M) (2 mL, 2.000mmol) was added and the mixture was heated at 45° C. for 1 hour. Thereaction mixture was acidified with 1 N HCl solution (2.5 mL), dilutedwith ethyl acetate, washed with brine, dried over anhydrous magnesiumsulfate, filtered and concentrated. The residue was purified by reversephase HPLC (C18, 0-100% CH₃CN/water (0.1% TFA)) to afford the titlecompound. ¹H NMR (300 MHz, CDCl₃) δ 9.16 (bs, 1H), 7.42 (d, J=2.6 Hz,1H), 7.37 (m, 2H), 7.16 (m, 1H), 7.01 (m, 2H), 6.98 (d, J=2.7 Hz, 1H),6.88 (d, J=8.5 Hz, 1H), 6.34 (s, 1H), 3.05 (s, 3H), 2.97 (m, 1H), 2.54(s, 3H), 2.50 (m, 2H), 2.26 (m, 2H), 1.14 (d, J=6.1 Hz, 3H). MS (ESI+)m/z 425.1 (M+H)⁺.

Example 68

3-methyl-6-(2-methylpropyl)-1-(2-phenoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 68 was prepared according to the procedure similar to that usedfor the preparation of Example 65, substituting2-acetyl-5-(2-methylpropyl)cyclohexane-1,3-dione for2-acetyl-5-methylcyclohexane-1,3-dione, to provide the title compound.¹H NMR (300 MHz, CDCl₃) δ 9.08 (bs, 1H), 7.52 (m, 1H), 7.34 (t, J=7.4Hz, 2H), 7.19-7.10 (m, 3H), 7.01 (d, J=7.2 Hz, 2H), 6.92 (m, 1H), 2.98(m, 1H), 2.54 (s, 3H), 2.51 (m, 2H), 2.21 (m, 2H), 1.72 (m, 1H), 1.31(t, J=6.8 Hz, 2H), 0.88 (d, J=6.4 Hz, 6H). MS (ESI+) m/z 467.2 (M+H)⁺.

Example 69N-{3-[3-methyl-6-(2-methylpropyl)-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl]-4-phenoxyphenyl}methanesulfonamideExample 69a

1-bromo-6-isobutyl-3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one. Example69a was prepared according to the procedure similar to that used for thepreparation of Example 65d, substituting2-acetyl-5-(2-methylpropyl)cyclohexane-1,3-dione for2-acetyl-5-methylcyclohexane-1,3-dione, to provide the title compound.

Example 69b

1-(5-amino-2-phenoxyphenyl)-6-isobutyl-3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one.Example 69b was prepared according to the procedure similar to that usedfor the preparation of Example 65e, substituting Example 69a for Example65d, and substituting4-phenoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for2-phenoxyphenylboronic acid, to provide the title compound.

Example 69c

N-{3-[3-methyl-6-(2-methylpropyl)-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl]-4-phenoxyphenyl}methanesulfonamide.Example 69c was prepared according to the procedure similar to that usedfor the preparation of Example 67, substituting Example 69b for Example66, to provide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 9.16 (bs,1H), 7.43 (d, J=2.3 Hz, 1H), 7.37 (m, 2H), 7.16 (m, 1H), 7.02 (m, 2H),6.97 (d, J=2.7 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 6.31 (s, 1H), 3.05 (s,3H), 2.98 (m, 1H), 2.54 (s, 3H), 2.51 (m, 2H), 2.22 (m, 2H), 1.74 (m,1H), 1.32 (t, J=7.1 Hz, 2H), 0.89 (d, J=6.5 Hz, 6H). MS (ESI+) m/z 467.2(M+H)⁺.

Example 70

3-methyl-1-(2-phenoxyphenyl)-6-(propan-2-yl)-2,5,6,7-tetrahydro-4H-isoindol-4-one.Example 70 was prepared according to the procedure similar to that usedfor the preparation of Example 65, substituting2-acetyl-5-(2-methylethyl)cyclohexane-1,3-dione for2-acetyl-5-methylcyclohexane-1,3-dione, to provide the title compound.¹H NMR (300 MHz, CDCl₃) δ 9.07 (bs, 1H), 7.52 (m, 1H), 7.34 (m, 2H),7.21-7.17 (m, 2H), 7.12 (m, 1H), 7.01 (m, 2H), 9.92 (m, 1H), 2.93 (m,1H), 2.58 (dd, J=11.2, 16.2 Hz, 1H), 2.54 (s, 3H), 2.48 (m, 1H), 2.29(dd, J=11.2, 16.2 Hz, 1H), 1.93 (m, 1H), 1.67 (m, 1H), 0.97 (d, J=6.8Hz, 6H). MS (ESI+) m/z 360.2 (M+H)⁺.

Example 71N-{3-[3-methyl-4-oxo-6-(propan-2-yl)-4,5,6,7-tetrahydro-2H-isoindol-1-yl]-4-phenoxyphenyl}methanesulfonamideExample 71a

1-bromo-6-isopropyl-3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one. Example71 a was prepared according to the procedure similar to that used forthe preparation of Example 65d, substituting2-acetyl-5-(2-methylethyl)cyclohexane-1,3-dione for2-acetyl-5-methylcyclohexane-1,3-dione, to provide the title compound.

Example 71b

1-(5-amino-2-phenoxyphenyl)-6-isopropyl-3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one.Example 71b was prepared according to the procedure similar to that usedfor the preparation of Example 65e, substituting Example 71a for Example65d, and substituting4-phenoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for2-phenoxyphenylboronic acid, to provide the title compound.

Example 71c

N-{3-[3-methyl-4-oxo-6-(propan-2-yl)-4,5,6,7-tetrahydro-2H-isoindol-1-yl]-4-phenoxyphenyl}methanesulfonamide.Example 71c was prepared according to the procedure similar to that usedfor the preparation of Example 67, substituting Example 71b for Example66, to provide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 9.18 (bs,1H), 7.49 (d, J=2.7 Hz, 1H), 7.37 (t, J=8.0 Hz, 2H), 7.27-7.21 (m, 2H),7.16 (m, 1H), 7.05-6.92 (m, 1H), 6.86 (m, 1H), 3.05 (s, 3H), 3.02 (m,1H), 2.59 (m, 1H), 2.54 (s, 3H), 2.51 (m, 1H), 2.29 (dd, J=11.2, 16.2Hz, 1H), 1.92 (m, 1H), 1.68 (m, 1H), 0.96 (d, J=4.8 Hz, 6H). MS (ESI+)m/z 453.2 (M+H)⁺.

Example 72N-[3-(3-methyl-4-oxo-6-phenyl-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamideExample 72a

1-bromo-6-phenyl-3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one. Example 72awas prepared according to the procedure similar to that used for thepreparation of Example 65d, substituting2-acetyl-5-phenylcyclohexane-1,3-dione for2-acetyl-5-methylcyclohexane-1,3-dione, to provide the title compound.

Example 72b

1-(5-amino-2-phenoxyphenyl)-6-phenyl-3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one.Example 72b was prepared according to the procedure similar to that usedfor the preparation of Example 65e, substituting Example 72a for Example65d, and substituting4-phenoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline for2-phenoxyphenylboronic acid, to provide the title compound.

Example 72c

N-[3-(3-methyl-4-oxo-6-phenyl-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamide.Example 72c was prepared according to the procedure similar to that usedfor the preparation of Example 67, substituting Example 72b for Example66, to provide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 9.12 (bs,1H), 7.48 (dd, J=7.4, 2.3 Hz, 1H), 7.38-7.31 (m, 5H), 7.29-7.23 (m, 1H),7.20-7.08 (m, 3H), 7.03-7.00 (m, 2H), 6.91 (m, 1H), 3.37 (m, 1H), 3.18(m, 1H), 3.07 (s, 3H), 3.00 (m, 1H), 2.82-2.67 (m, 2H), 2.58 (s, 3H). MS(ESI+) m/z 487.1 (M+H)⁺.

Example 731-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-oneExample 73a

1-(2-fluoro-5-(methylsulfonyl)phenyl)-3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one.A 5 mL microwave tube equipped with a stir bar was charged with3-methyl-6,7-dihydro-2H-isoindol-4(5H)-one (0.217 g, 1.455 mmol),2-bromo-1-fluoro-4-(methylsulfonyl)benzene (0.253 g, 1.000 mmol),allylpalladium(II) chloride (0.0176 g, 0.048 mmol) and potassium acetate(0.329 g, 3.35 mmol), sealed, and purged with nitrogen. DegassedN,N-dimethylacetamide (5 ml) was introduced, and the vessel was placedin an oil bath and stirred for 18 hours at 130° C. The reaction mixturewas cooled and shaken in a separatory funnel with 60 mL each of EtOAcand brine. The organics were washed twice with brine and dried oversodium sulfate. After filtration the mixture was concentrated andchromatographed on a 40 g silica cartridge eluting with 0-100%EtOAc/heptane to provide the title compound.

Example 73b

1-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.A 5 mL microwave reaction vessel equipped with a stir bar was chargedwith sodium hydride (dry, 95% 16.8 mg, 0.665 mmol) suspended in THF (0.5mL), then cyclopropylmethanol (35 μL, 0.432 mmol) and sealed. Afterstirring for 10 minutes, Example 73a (70 mg, 0.218 mmol) in THF (2.0 mL)was added. The mixture was heated at 60° C. in an oil bath for 20 hours.The mixture was cooled and partitioned between 60 mL each of EtOAc andbrine. The organics were dried over magnesium sulfate. After filtrationand solvent removal the residue was purified by reverse phase HPLC (C18,0-100% CH₃CN/water (0.1% TFA)) to afford the title compound. ¹H NMR (300MHz, DMSO-d₆) δ ppm 11.34 (bds, 1H), 7.80-7.71 (m, 2H), 7.26 (d, J=8.8Hz, 1H), 3.98 (d, J=7.1 Hz, 2H), 3.18 (s, 3H), 2.64 (t, J=5.9 Hz, 2H),2.28 (s, 3H), 2.33 (m, 2H), 1.91 (m, 2H), 1.25 (m, 1H), 0.57 (m, 2H),0.36 (m, 2H). MS (ESI+) m/z 374.1 (M+H)⁻.

Biological Examples Bromodomain Domain Binding Assay

A time-resolved fluorescence resonance energy transfer (TR-FRET) assaywas used to determine the affinities of compounds of the Examples listedin Table 1 for each bromodomain of BRD4. His-tagged first (BD1: aminoacids K57-E168) and second (BD2: amino acids E352-E168) bromodomains ofBRD4 were expressed and purified. An Alexa647-labeled BET-inhibitor wasused as the fluorescent probe in the assay.

Synthesis of Alexa647-labeled bromodomain inhibitor compound2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid._Methyl2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate(see e.g., WO 2006129623)(100.95 mg, 0.243 mmol was suspended in 1 mLmethanol to which was added a freshly prepared solution of lithiumhydroxide monohydrate (0.973 mL, 0.5 M, 0.487 mmol) and shaken atambient temperature for 3 hours. The methanol was evaporated and the pHadjusted with aqueous hydrochloric acid (1 M, 0.5 mL, 0.5 mmol) andextracted four times with ethyl acetate. The combined ethyl acetatelayers were dried over magnesium sulfate and evaporated to afford2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid (85.3 mg, 87.0%); ESI-MS m/z =401.1 [(M+H)⁺] which was useddirectly in the next reaction.

N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,24][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate).2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)aceticacid)(85.3 mg, 0.213 mmol) was combined with2,2′-(ethane-1,2-diylbis(oxy))diethanamine (Sigma-Aldrich, 0.315 mg,2.13 mmol) were combined in 5 mL anhydrous dimethylformamide.(1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphoniumhexafluorophosphate(V) (PyBOB, CSBio, Menlo Park Calif.; 332 mg, 0.638mmol) was added and the reaction shaken at ambient temperature for 16hours. The reaction was diluted to 6 mL with dimethylsulfoxide:water(9:1, v:v) and purified in two injections with time collection WatersDeltapak C 18 200×25 mm column eluted with a gradient of 0.1%trifluoroacetic acid (v/v) in water and acetonitrile. The fractionscontaining the two purified products were lyophilized to affordN-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate) (134.4 mg, 82.3%); ESI-MS m/z=531.1[(M+H)⁺]; 529.1 [(M−H)⁻] and(S,Z)—N,N′-(2,2′-(ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide)bis(2,2,2-trifluoroacetate) (3.0 mg, 1.5%); ESI-MS m/z=913.2 [(M+H)⁺];911.0 [(M−H)⁻].

N-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide(2,2,2-trifluoroacetate)._(—)N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamidebis(2,2,2-trifluoroacetate) (5.4 mg, 0.0071 mmol) was combined withAlexa Fluor® 647 carboxylic Acid, succinimidyl ester (Life Technologies,Grand Island, N.Y.; 3 mg, 0.0024 mmol) were combined in 1 mL anhydrousdimethylsulfoxide containing diisopropylethylamine (1% v/v) and shakenat ambient temperature for 16 hours. The reaction was diluted to 3 mLwith dimethylsulfoxide:water (9:1, v:v) and purified in one injectionwith time collection Waters Deltapak C18 200×25 mm column eluted with agradient of 0.1% trifluoroacetic acid (v/v) in water and acetonitrile.The fractions containing the purified product were lyophilized to affordN-(2-(2-(2-amido-(Alexa647)-ethoxy)ethoxy)ethyl)-24(6S,Z)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide(2,2,2-trifluoroacetate)(1.8 mg); MALDI-MS m/z=1371.1, 1373.1 [(M+H)⁺] as a dark blue powder.

Assay

Compound dilution series were prepared in DMSO via a 3-fold serialdilution from 2.5 mM to 42 nM. Compounds were then diluted 6:100 inassay buffer (20 mM Sodium Phosphate, pH 6.0, 50 mM NaCl, 1 mM EDTA,0.01% Triton X-100, 1 mM DTT) to yield 3× working solutions. Sixmicroliters (μL) of the working solution was then transferred to white,low-volume assay plates (Costar #3673). A 1.5× assay mixture containingHis-tagged bromodomain, Europium-conjugated anti-His antibody(Invitrogen PV5596) and the Alexa-647-conjugated probe molecule was alsoprepared. Twelve μL of this solution were added to the assay plate toreach a final volume of 18 μL. The final concentration of 1× assaybuffer contains 2% DMSO, 50 μM-0.85 nM compound, 8 nM bromodomain, 1 nMantibody and 100 or 30 nM probe (for BDI or BDII, respectively). After aone-hour incubation at room temperature, TR-FRET ratios were determinedusing an Envision multilabel plate reader (Ex 340, Em 495/520).

TR-FRET data were normalized to the means of 24 no-compound controls(“high”) and 8 controls containing 1 μM un-labeled probe (“low”).Percent inhibition was plotted as a function of compound concentrationand the data were fit with the 4 parameter logistic equation to obtainIC₅₀s. Inhibition constants (K_(i)) were calculated from the IC₅₀s,probe K_(d) and probe concentration. Typical Z′ values were between 0.65and 0.75. The minimum significant ratio was determined to evaluate assayreproducibility (Eastwood et al., (2006) J Biomol Screen, 11: 253-261).The MSR was determined to be 2.03 for BDI and 1.93 for BDII, and amoving MSR (last six run MSR overtime) for both BDI and BDII wastypically <3. The K_(i) values are reported in Table 1.

MX-1 Cell Line Proliferation Assay

The impact of compounds of the Examples on cancer cell proliferation wasdetermined using the breast cancer cell line MX-1 (ATCC) in a 3-dayproliferation assay. MX-1 cells were maintained in RPMI supplementedwith 10% FBS at 37° C. and an atmosphere of 5% CO₂. For compoundtesting, MX-1 cells were plated in 96-well black bottom plates at adensity of 5000 cells/well in 90 μl of culture media and incubated at37° overnight to allow cell adhesion and spreading. Compound dilutionseries were prepared in DMSO via a 3-fold serial dilution from 3 mM to0.1 μM. The DMSO dilution series were then diluted 1:100 in phosphatebuffered saline, and 10 μL of the resulted solution were added to theappropriate wells of the MX-1 cell plate. The final compoundconcentrations in the wells were 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003,0.001, 0.0003 and 0.0001 μM. After the addition of compounds, the cellswere incubated for 72 more hours and the amounts of viable cells weredetermined using the Cell Titer Glo assay kit (Promega) according tomanufacturer suggested protocol.

Luminescence readings from the Cell Titer Glo assay were normalized tothe DMSO treated cells and analyzed using the GraphPad Prism softwarewith sigmoidal curve fitting to obtain EC₅₀s. The minimum significantratio (MSR) was determined to evaluate assay reproducibility (Eastwoodet al., (2006) J Biomol Screen, 11: 253-261). The overall MSR wasdetermined to be 2.1 and a moving MSR (last six run MSR overtime) hasbeen <2. The EC₅₀ values are reported in Table 1.

TABLE 1 TR-FRET Binding TR-FRET Binding Cellular Ki: BRD4 Ki: BRD4proliferation: (BDI_K57-E168) (BDII_E352-M457) EC₅₀ Example # (μM) (μM)(μM) 1 3.68 3.07 3.4 2 0.255 0.504 1.43 3 3.73 15.0 N/A 4 2.49 15.9 N/A5 1.4 2.03 3.7 6 2.7 9.97 N/A 7 0.261 0.805 0.676 8 1.43 3.82 2.5 90.961 3.1 2.75 10 1.79 4.06 1.23 11 1.88 5.46 N/A 12 2.86 10.4 N/A 137.29 22.2 N/A 14 9.06 22.2 N/A 15 1.14 22.2 N/A 16 3.77 8.42 N/A 17 5.5117.5 N/A 18 0.943 2.03 1.23 19 0.943 19.7 3.18 20 1.77 4.49 N/A 21 1.865.92 N/A 22 2.47 8.21 N/A 23 9.09 8.92 N/A 24 1.2 2.3 N/A 25 4.24 15.1N/A 26 6.22 10.4 N/A 27 2.76 6.58 N/A 28 5.31 15.05 N/A 29 0.3152.92 >3.0 30 1.25 4.78 N/A 31 0.765 4.68 >3.0 32 0.202 1.94 1.88 33 1.048.16 >3.0 34 1.35 2.62 >3.0 35 9.14 11.0 N/A 36 8.83 9.73 N/A 37 0.5264.14 >3.0 38 4.88 4.86 N/A 39 0.148 0.365 0.232 40 0.015 0.043 0.16 410.161 0.216 0.37 42 0.569 1.09 >3.0 43 1.82 0.568 >3.0 44 0.067 0.0370.645 45 0.04 0.198 0.329 46 0.014 0.052 0.238 47 0.011 0.019 0.193 480.068 0.043 0.564 49 0.043 0.192 0.364 50 0.071 0.551 0.609 51 0.1640.943 N/A 52 0.009 0.088 0.184 53 0.927 3.67 N/A 54 0.045 0.289 N/A 550.077 0.511 1.39 56 0.068 0.653 0.734 57 1.07 22.2 N/A 58 0.932 0.513N/A 59 3.23 2.52 N/A 60 3.37 2.7 N/A 61 2.2 1.68 N/A 62 1.5 1.75 N/A 630.786 1.03 N/A 64 0.576 0.409 >3.0 65 0.184 0.382 1.78 66 0.058 0.069N/A 67 0.012 0.068 0.11 68 3.62 22.2 N/A 69 0.151 2.07 0.60 70 1.2 2.22N/A 71 0.375 0.926 0.95 72 7.28 22.2 N/A 73 0.034 0.461 N/A

Proliferation Panel Assay.

The compound of Example 40 was tested for its impact on proliferation ofa panel of cancer cell line types (with specific cell lines tested) asset out in (Table 2). Cells were plated in 96-well plates at 1500cells/well in the appropriate culture media. Series dilutions ofcompound were prepared and added to the wells as in the MX-1proliferation assay. After the addition of the compound, cells wereincubated for another 5 days and the amounts of viable cells weredetermined using the Cell Titer Glo assay kit (Promega) according tomanufacturer suggested protocol. Cell proliferation data were analyzedas described above in the MX-1 proliferation assay to obtain the EC₅₀for the compounds reported in Table 2.

TABLE 2 Compound of Example 40 Cellular Proliferation Cell line TypeCell Line EC₅₀ (μM) AML Raji 0.036 AML SKM1 0.039 Bladder EJ-1 0.594Breast MDAMB231 0.31 Breast MDAMB453 0.22 Colon DLD-1 0.45 Colon GEO0.38 Glioblastoma D54MG 0.210 Head & Neck FaDu 0.18 Hepatocellular HepG20.32 Melanoma A-375 0.168 Multiple NCI-H929 0.041 Myeloma Multiple OPM20.018 Myeloma Multiple RPMI-8226 0.094 Myeloma NHL Ly18 0.37 NHL Ramos0.34 NSCLC H1299 0.36 NSCLC H1975 0.18 NSCLC H460 >10 Pancreas BxPC3FP50.07 Pancreas HPAC 0.29 Prostate PC3M 0.41 RCC 786-0 0.139 SarcomaSK-LMS-1 0.176

Xenograft Tumor Growth Inhibition Assay

The effect of the compound of Example 40 to inhibit the growth of Ramos,OPM-2, MX-1, MV4-11, and HT1080 xenograft tumors was evaluated. Briefly,0.5×10⁶ human cancer cells (HT1080), 1×10⁶ human cancer cells (Ramos),5×10⁶ human cancer cells (OPM-2, MV4-11) or 1:10 tumor brie (MX-1) (inS-MEM (MEM, Suspension, no Calcium, no Glutamine))(Life TechnologiesCorporation) were inoculated subcutaneously into the right hind flank offemale SCID or SCID-beige (MV4-11, HT1080) mice (Charles Rivers Labs) onstudy day 0. Compound was formulated in 2% EtOH, 5% Tween-80, 20%PEG-400, 73% HPMC (Ramos, OPM-2 and MX-1) or 5% DMSO, 5% EtOH, 30%PEG400, 60% Phosal 53 (MV4-11, HT1080). Administration of compound wasinitiated at the time of size match on day 8 (HT1080), day 17 (MX-1), orday 18 (Ramos, MV4-11, OPM-2). The tumors were measured by a pair ofcalipers twice a week starting at the time of size match and tumorvolumes were calculated according to the formula V=L×W²/2 (V: volume,mm³; L: length, mm. W: width, mm). Tumor volume was measured for theduration of the experiment until the mean tumor volume in each groupreached an endpoint of >1000 mm³. Results are shown in Tables 3-7.

TABLE 3 Ramos human B cell lymphoma cancer xenograft model % % GroupTreatment Dose route, regimen TGI ^(a) TGD ^(b) 1 Vehicle 0 mg/kg/dayPO, QDx14 — — 2 Compound of 100 mg/kg/day PO, QDx14 30*  40*  Example 403 Compound of 100 mg/kg/day PO, BID 35*** 40** Example 40 (5on 3off) x 2^(a) Tumor growth inhibition, % TGI = 100 − mean tumor volume oftreatment group/mean tumor volume of control group × 100. The p values(as indicated by asterisks) are derived from Student's T test comparisonof treatment group vs. control group. Based on day 31. *p < 0.05, **p <0.01, ***p < 0.001. ^(b) Tumor growth delay, % TGD = (T − C)/C × 100,where T = median time to endpoint of treatment group and C = median timeto endpoint of control group. The p values (as indicated by asterisks)derived from Kaplan Meier log-rank comparison of treatment group vs.treatment control group. Based on an endpoint of 1000 mm³. *p < 0.05,**p < 0.01, ***p < 0.001.

TABLE 4 OPM-2 human multiple myeloma cancer xenograft model % % GroupTreatment Dose route, regimen TGI ^(a) TGD ^(b) 1 Vehicle 0 mg/kg/dayPO, QDx14 — — 2 Compound of 100 mg/kg/day PO, 41**    88*** Example 40QDx14 3 Compound of 30 mg/kg/day PO, 27*  63 Example 40 QDx14 4 Compoundof 10 mg/kg/day PO, 16  25 Example 40 QDxl4 5 Compound of 100 mg/kg/dayPO, 43**  175*** Example 40 BIDx14 6 Compound of 30 mg/kg/day PO, 31*  88* Example 40 BIDx14 7 Compound of 10 mg/kg/day PO, 11  25 Example 40BIDx14 ^(a) Tumor growth inhibition, % TGI = 100 − mean tumor volume oftreatment group/mean tumor volume of control group × 100. The p values(as indicated by asterisks) are derived from Student's T test comparisonof treatment group vs. control group. Based on day 31. *p < 0.05, **p <0.01, ***p < 0.001. ^(b) Tumor growth delay, % TGD = (T − C)/C × 100,where T = median time to endpoint of treatment group and C = median timeto endpoint of control group. The p values (as indicated by asterisks)derived from Kaplan Meier log-rank comparison of treatment group vs.treatment control group. Based on an endpoint of 1000 mm³. *p < 0.05,**p < 0.01, ***p < 0.001.

TABLE 5 Efficacy of BET inhibitor in the MX-1 human breast cancerxenograft model % % Group Treatment Dose route, regimen TGI^(a) TGD ^(b)1 Vehicle 0 mg/kg/day PO, QDx14 — — 2 Compound of 100 mg/kg/day PO,QDx14 78*** 29*** Example 40 3 Compound of 30 mg/kg/day PO, QDx14 48***22*** Example 40 4 Compound of 10 mg/kg/day PO, QDx14 18   17    Example40 5 Compound of 100 mg/kg/day PO, QDx14 80*** 28*** Example 40 6Compound of 20 mg/kg/day PO, QDx14 30*  19*  Example 40 ^(a)Tumor growthinhibition, % TGI = 100 − mean tumor volume of treatment group/meantumor volume of control group × 100. The p values (as indicated byasterisks) are derived from Student's T test comparison of treatmentgroup vs. control group. Based on day 38. *p < 0.05, **p < 0.01, ***p <0.001. ^(b) Tumor growth delay, % TGD = (T − C)/C × 100, where T =median time to endpoint of treatment group and C = median time toendpoint of control group. The p values (as indicated by asterisks)derived from Kaplan Meier log-rank comparison of treatment group vs.treatment control group. Based on an endpoint of 1000 mm³. *p < 0.05,**p < 0.01, ***p < 0.001.

TABLE 6 Efficacy of BET inhibitor in the HT1080 human fibrosarcomaxenograft model. % Group Treatment Dose route, regimen TGI^(a) 1 Vehicle0 mg/kg/day PO, QDx14 — 2 Compound of 10 mg/kg/day PO, BID x 14 −1Example 40 3 Compound of 30 mg/kg/day PO, BID x 14 14 Example 40 4Compound of 100 mg/kg/day PO, BID x 14  52** Example 40 ^(a)Tumor growthinhibition, % TGI = 100 − mean tumor volume of treatment group/meantumor volume of control group × 100. The p values (as indicated byasterisks) are derived from Student's T test comparison of treatmentgroup vs. control group. Based on day 18. **p < 0.01.

TABLE 7 Efficacy of BET inhibitor in the MV4-11 human AML xenograftmodel % Group Treatment Dose route, regimen TGI^(a) 1 Vehicle 0mg/kg/day PO, QDx14 — 2 Compound of 25 mg/kg/day PO, BID x 14 14^(b) Example 40 3 Compound of 50 mg/kg/day PO, BID x 14 42^(c)** Example 40 4Compound of 100 mg/kg/day PO, BID 67^(d)** Example 40 5 on, 3 off x 2^(a)Tumor growth inhibition, % TGI = 100 − mean tumor volume oftreatment group/mean tumor volume of control group × 100. The p values(as indicated by asterisks) are derived from Student's T test comparisonof treatment group vs. control group. Based on day 31. **p < 0.01.^(b)10% mortality. ^(c)30% mortality ^(d)40% mortality

LPS (Lipopolysaccharide) Induced IL-6 Production Mouse Assay

Compounds of the Examples listed in Table 8 were assayed for theirability to inhibit LPS (lipopolysaccharide) induced IL-6 production inmice. Severe combined immunodeficient female mice (8 per group) receivedan intraperitoneal challenge of lipopolysaccharide (2.5 mg/kg, L2630 E.coli 0111:B4) one hour after oral administration (PO) or intraperitonealadministration (IP) of compounds in a solution of 2% ethanol, 5%Tween-80, 20% PEG-400 and 73% (0.2% hydroxypropylmethylcellulose inwater). Mice were euthanized 2 hours after lipopolysaccharide injection,blood was removed by cardiac puncture, and then the serum harvested fromthe blood samples was frozen at −80° C. On the day of the assay theserum samples were brought to room temperature and then diluted 1:20 inphosphate-buffered saline containing 2% bovine serum albumin.Interleukin-6 measurements were performed using a cytokine assay fromMeso Scale Discovery (Gaithersburg, Md.) for mouse serum analysisaccording to the manufacturer's protocol and read on a SECTOR Imager6000 (Meso Scale Discovery, Gaithersburg, Md.) instrument. Statisticalanalysis was performed using Prism software (version 5.0) incorporatingDunnett's one way ANOVA. The IL-6 mean and standard deviation of thegroup of vehicle treated animals were compared with the IL-6 mean andstandard deviation of the group treated with drug. A p value <0.05 meansthat there is less than a 5% probability that the mean values in the twogroups are equal. The % inhibition values in Table 8 all exhibited a pvalue less than 0.05.

TABLE 8 Inhibition of LPS induced IL-6 production Compound of ExampleNo. % inhibition 40 84.7 at 50 mg/kg (IP) 40 72.7 at 30 mg/kg (PO) 4052.4 at 10 mg/kg (PO) 40 28.7 at 3 mg/kg (PO) 47 33.0 at 3 mg/kg (PO)

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof. All publications, patents, and patent applications citedherein are hereby incorporated by reference in their entirety for allpurposes.

1. A compound of formula (I), or a pharmaceutically acceptable saltthereof

wherein A is C(R⁸R⁹); Y is C(R⁶R⁷); J is C(R⁴R⁵); R¹ is hydrogen orC₁-C₃ alkyl; R² is hydrogen or C₁-C₃ alkyl; R³ is heteroaryl, 9 to 12membered bicyclic aryl, napthalen-1yl, unsubstituted phenyl, or X,wherein X is

wherein said heteroaryl, 9 to 12 membered bicyclic aryl, ornapthalen-1-yl may be substituted with one to three substituentsindependently selected from the group consisting of NR¹⁶R¹⁸, halo,hydroxyl, C₁-C₃ alkyl, —O-aryl, C₁-C₃ alkylene-aryl, C₁-C₃alkylene-aryl, C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₁-C₃ alkylene-aryl,—NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl,—NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl, 50₂—NR¹⁶R¹⁸,SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃ alkyl, —C(O)—OH,—C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl), —C(O)—NH(C₁-C₃alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl), —NH—C(O)—C₁-C₃ alkyl,—NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃alkylene-heterocycloalkyl, —O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃alkylene-C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkylene-heteroaryl, or heteroaryl;wherein X is substituted as set out in (i) or (ii): (i) four of R¹⁰,R¹¹, R¹², R¹³, and R¹⁴ are hydrogen, and one of R¹⁰, R¹¹, R¹², R¹³, orR¹⁴ is selected from the following groups: R¹⁰ is NR¹⁶R¹⁸, halo,hydroxyl, C₁-C₃ alkyl, C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl,—S-aryl, —O—C₁-C₃ alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl,—NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃haloalkyl, SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃ alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃alkyl, —C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl),—C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl),NH—C(O)—C₁-C₃ alkyl, NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃alkylene-heterocycloalkyl, —O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkyleneC₃-C₅cycloalkyl, C₁-C₃ alkyleneC₇-C₁₄ cycloalkyl, —O—C₁-C₃alkylene-heteroaryl, or heteroaryl; R¹¹ is NR¹⁶R¹⁸, fluoro, iodo, bromo,hydroxyl, C₁-C₃ alkyl, —O-aryl, C₁-C₃ alkylene-aryl, C₁-C₃alkylene-O-aryl, —S-aryl, —O—C₁-C₃ alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl,—NR¹⁶—SO₂—C₁-C₃ haloalkyl, SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl,—C(O)—O—C₁-C₃ alkyl, —C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl),—C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl),NH—C(O)—C₁-C₃ alkyl, NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃alkylene-heterocycloalkyl, —O—C₁-C₃ alkyleneC₃-C₁₄ cycloalkyl, —O—C₁-C₃alkylene-heteroaryl, or heteroaryl; R¹² is NR¹⁶R¹⁸, halo, hydroxyl,C₁-C₃ alkyl, C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl, —S-aryl,—O—C₂-C₃ alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl,SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃ alkyl,—C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl), —C(O)—NH(C₁-C₃alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl), NH—C(O)—C₁-C₃ alkyl,NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃alkylene-heterocycloalkyl,—O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkylene-C₃-C₁₄cycloalkyl, —O—C₁-C₃ alkylene-heteroaryl, or heteroaryl; R¹³ and R¹⁴ areNR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, —O-aryl, C₁-C₃ alkylene-aryl,C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₁-C₃ alkylene-aryl,—NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl,—NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl, SO₂—NR¹⁶R¹⁸,SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃ alkyl, —C(O)—OH,—C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl), —C(O)—NH(C₁-C₃alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl), NH—C(O)—C₁-C₃ alkyl,NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃alkylene-heterocycloalkyl, —O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃alkylene-C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkylene-heteroaryl, or heteroaryl;(ii) wherein 5-n of R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are hydrogen, and n ofR¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are selected from the following groups:NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, —O-aryl, C₁-C₃ alkylene-aryl,C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₁-C₃ alkylene-aryl,—NR¹⁶—SO₂—NR¹⁶-C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl,—NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl, SO₂—NR¹⁶R¹⁸,SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃ alkyl, —C(O)—OH,—C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl), —C(O)—NH(C₁-C₃alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl), NH—C(O)—C₁-C₃ alkyl,NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃alkylene-heterocycloalkyl,—O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkylene-C₃-C₁₄cycloalkyl, —O—C₁-C₃ alkylene-heteroaryl, or heteroaryl; wherein n is 2,3, 4 or 5; wherein any of said aryl groups of —O-aryl, —S-aryl, C₁-C₃alkylene-aryl, C₁-C₃ alkylene-O-aryl; said heterocycloalkyl; saidheterocycloalkyl groups of —C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl) and—O—C₁-C₃ alkylene-heterocycloalkyl; said heteroaryl; said heteroarylgroups of —C(O)—NH(heteroaryl), NH—C(O)-heteroaryl, and —O—C₁-C₃alkylene-heteroaryl; and said cycloalkyl groups of —O—C₃-C₁₄ cycloalkyl,—O—C₁-C₃ alkyleneC₃-C₅ cycloalkyl, and —O—C₁-C₃ alkyleneC₃-C₁₄cycloalkyl may be subsitituted with 1 to 3 subsitituents selected fromthe group consisting of: halo, C₁-C₃ alkyl, C₁-C₃ haloalkyl, CN, andNR¹⁶R¹⁸; R⁴ and R⁵ are each independently selected from hydrogen, aryl,and C₁-C₄ alkyl; R⁶ and R⁷ are each independently selected from hydrogenand C₁-C₄ alkyl; R⁸ and R⁹ are each independently selected from hydrogenand C₁-C₄ alkyl; and R¹⁶ and R¹⁸ are each independently selected fromhydrogen and C₁-C₃ alkyl.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁴ and R⁵ arehydrogen; and R⁸ and R⁹ are each hydrogen.
 3. The compound of claim 2,or a pharmaceutically acceptable salt thereof, wherein R² is hydrogen.4. The compound of claim 3, or a pharmaceutically acceptable saltthereof, wherein R¹ is C₁-C₃ alkyl.
 5. The compound of claim 4, or apharmaceutically acceptable salt thereof, wherein R¹ is methyl.
 6. Thecompound of claim 5, or a pharmaceutically acceptable salt thereof,wherein R¹³ is NR¹⁶R¹⁸, NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl,SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl),—C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl),NH—C(O)—C₁-C₃ alkyl, or NH—C(O)-heteroaryl.
 7. The compound of claim 6,or a pharmaceutically acceptable salt thereof, wherein R¹³ is N¹⁶R¹⁸,—NR¹⁶—SO₂—C₁-C₃ alkyl, or —NH—SO₂—C₁-C₃ haloalkyl.
 8. The compound ofclaim 5, or a pharmaceutically acceptable salt thereof, wherein R³ isheteroaryl, 9 to 12 membered bicyclic aryl, or napthalen-1-yl.
 9. Thecompound of claim 5, or a pharmaceutically acceptable salt thereof,wherein R³ is indolyl, 1,3-benzodioxolyl, or benzimidazolyl.
 10. Thecompound of claim 7, or a pharmaceutically acceptable salt thereof,wherein R³ is X.
 11. The compound of claim 10, or a pharmaceuticallyacceptable salt thereof, wherein four of R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ arehydrogen, and one of R¹⁰, R¹¹, R¹², R¹³, or R¹⁴ is selected from thefollowing groups: R¹⁰ is NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, C₁-C₃alkylene-aryl, C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₁-C₃ alkylene-aryl,—NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl,—NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl, SO₂—NR¹⁶R¹⁸,SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃ alkyl, —C(O)—OH,—C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl), —C(O)—NH(C₁-C₃alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl), NH—C(O)—C₁-C₃ alkyl,NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃alkylene-heterocycloalkyl, —O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkyleneC₃-0₅cycloalkyl, C₁-C₃ alkyleneC₇-C₁₄ cycloalkyl, —O—C₁-C₃alkylene-heteroaryl, or heteroaryl; R¹¹ is NR¹⁶R¹⁸, fluoro, iodo, bromo,hydroxyl, C₁-C₃ alkyl, —O-aryl, C₁-C₃ alkylene-aryl, C₁-C₃alkylene-O-aryl, —S-aryl, —O—C₁-C₃ alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl,—NR¹⁶—SO₂—C₁-C₃ haloalkyl, SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl,—C(O)—O—C₁-C₃ alkyl, —C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl),—C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl),NH—C(O)—C₁-C₃ alkyl, NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃alkylene-heterocycloalkyl, —O—C₁-C₃ alkyleneC₃-C₁₄ cycloalkyl, —O—C₁-C₃alkylene-heteroaryl, or heteroaryl; R¹² is NR¹⁶R¹⁸, halo, hydroxyl,C₁-C₃ alkyl, C₁-C₃ alkylene-aryl, C₁-C₃ alkylene-O-aryl, —S-aryl,—O—C₂-C₃ alkylene-aryl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl,SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃ alkyl,—C(O)—OH, —C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl), —C(O)—NH(C₁-C₃alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl), NH—C(O)—C₁-C₃ alkyl,NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃alkylene-heterocycloalkyl,—O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkylene-C₃-C₁₄cycloalkyl, —O—C₁-C₃ alkylene-heteroaryl, or heteroaryl; R¹³ and R¹⁴ areNR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, —O-aryl, C₁-C₃ alkylene-aryl,C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₁-C₃ alkylene-aryl,—NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl,—NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl, SO₂—NR¹⁶R¹⁸,SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃ alkyl, —C(O)—OH,—C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl), —C(O)—NH(C₁-C₃alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl), NH—C(O)—C₁-C₃ alkyl,NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃alkylene-heterocycloalkyl, —O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃alkylene-C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkylene-heteroaryl, or heteroaryl;and wherein any of said aryl groups of —O-aryl, —S-aryl, C₁-C₃alkylene-aryl, C₁-C₃ alkylene-O-aryl; said heterocycloalkyl; saidheterocycloalkyl groups of —C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl) and—O—C₁-C₃ alkylene-heterocycloalkyl; said heteroaryl and said heteroarylgroups of —C(O)—NH(heteroaryl), NH—C(O)-heteroaryl, and —O—C₁-C₃alkylene-heteroaryl; and said cycloalkyl groups of —O—C₃-C₁₄ cycloalkyl,—O—C₁-C₃ alkyleneC₃-C₅ cycloalkyl, and —O—C₁-C₃ alkyleneC₃-C₁₄cycloalkyl may be subsitituted with 1 to 3 subsitituents selected fromthe group consisting of: halo, C₁-C₃ alkyl, C₁-C₃ haloalkyl, CN, andNR¹⁶R¹⁸.
 12. The compound of claim 10, or a pharmaceutically acceptablesalt thereof, wherein 5-n of R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are hydrogen,and n of R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are selected from the followinggroups: NR¹⁶R¹⁸, halo, hydroxyl, C₁-C₃ alkyl, —O-aryl, C₁-C₃alkylene-aryl, C₁-C₃ alkylene-O-aryl, —S-aryl, —O—C₁-C₃ alkylene-aryl,—NR¹⁶—SO₂—NR¹⁸—C₁-C₃ alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl,—NR¹⁶—SO₂—C₁-C₃ alkyl, —NR¹⁶—SO₂—C₁-C₃ haloalkyl, SO₂—NR¹⁶R¹⁸,SO₂—C₁-C₃alkyl, —O—C₁-C₃ alkyl, —C(O)—O—C₁-C₃ alkyl, —C(O)—OH,—C(O)—NR¹⁶R¹⁸, —C(O)—NH(C₁-C₃ haloalkyl), —C(O)—NH(C₁-C₃alkylene-heterocycloalkyl), —C(O)—NH(heteroaryl), NH—C(O)—C₁-C₃ alkyl,NH—C(O)-heteroaryl, heterocycloalkyl, —O—C₁-C₃alkylene-heterocycloalkyl,—O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkylene-C₃-C₁₄cycloalkyl, —O—C₁-C₃ alkylene-heteroaryl, or heteroaryl; wherein n is 2,3, 4 or 5; wherein any of said aryl groups of —O-aryl, —S-aryl, C₁-C₃alkylene-O-aryl; said heterocycloalkyl groups of —C(O)—NH(C₁-C₃alkylene-heterocycloalkyl) and —O—C₁-C₃ alkylene-heterocycloalkyl; saidheteroaryl and said heteroaryl groups of —C(O)—NH(heteroaryl),NH—C(O)-heteroaryl, and —O—C₁-C₃ alkylene-heteroaryl; and saidcycloalkyl groups of —O—C₃-C₁₄ cycloalkyl, —O—C₁-C₃ alkylene-C₃-C₅cycloalkyl, and —O—C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl may be subsititutedwith 1 to 3 subsitituents selected from the group consisting of: halo,C₁-C₃ alkyl, C₁-C₃ haloalkyl, CN, and NR¹⁶R¹⁸.
 13. The compound of claim12, or a pharmaceutically acceptable salt thereof, wherein n is
 3. 14.The compound of claim 12, or a pharmaceutically acceptable salt thereof,wherein n is
 2. 15. The compound of claim 14, or a pharmaceuticallyacceptable salt thereof, wherein R¹³ is NR¹⁶R¹⁸, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃alkyl, —NR¹⁶—SO₂—NR¹⁸—C₁-C₃ haloalkyl, —NR¹⁶—SO₂—C₁-C₃ alkyl,—NR¹⁶—SO₂—C₁-C₃ haloalkyl, SO₂—NR¹⁶R¹⁸, SO₂—C₁-C₃alkyl, —C(O)—NR¹⁶R¹⁸,—C(O)—NH(C₁-C₃ haloalkyl), —C(O)—NH(C₁-C₃ alkylene-heterocycloalkyl),—C(O)—NH(heteroaryl), NH—C(O)—C₁-C₃ alkyl, or NH—C(O)-heteroaryl. 16.The compound of claim 15, or a pharmaceutically acceptable salt thereof,wherein R¹³ is NR¹⁶R¹⁸, —NR ¹⁶—SO₂—C₁-C₃ SO₂—C₁-C₃ alkyl, or—NH—SO₂—C₁-C₃ haloalkyl.
 17. The compound of claim 16, or apharmaceutically acceptable salt thereof, wherein R¹⁰ is O-aryl.
 18. Thecompound of claim 17, or a pharmaceutically acceptable salt thereof,wherein R¹⁰ is O-phenyl or is O-phenyl which is substituted with 1 to 3independently groups independently selected from the group consisting ofhalo.
 19. The compound of claim 18, or a pharmaceutically acceptablesalt thereof, wherein R¹⁰ is —O-2,4-difluoro-phenyl.
 20. The compound ofclaim 16, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ is—O—C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl, which may be substituted with 1 to3 groups independently selected from the group consisting of halo andC₁-C₃ alkyl.
 21. The compound of claim 20, or a pharmaceuticallyacceptable salt thereof, wherein R¹⁰ is —O—C₁-C₃ alkylene-C₃-C₁₄cycloalkyl, which is substituted with 1 to 3 groups independentlyselected from the group consisting of halo and C₁-C₃ alkyl.
 22. Thecompound of claim 21, or a pharmaceutically acceptable salt thereof,wherein R¹⁰ is —O—C₁-C₃ alkylene-C₃-C₁₄ cycloalkyl, which is substitutedwith 1 to 3 groups independently selected from the group consisting ofhalo.
 23. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein n is
 3. 24. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein n is 2 and R¹¹, R¹²,and R¹⁴ are hydrogen.
 25. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein said compound is selected from thegroup consisting of:3-methyl-1-phenyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-(2-phenoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-(2-aminophenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-(4-methylphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;4-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)benzenesulfonamide;1-(2-methoxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1(3,4,5-trimethoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-[4-(methylsulfonyl)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)benzamide;1-(1H-indol-4-yl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-(4-methoxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-(3,4-dimethylphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-(4-chlorophenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-[3-(benzyloxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-(2-chlorophenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-(3,5-dimethylphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-(3-methoxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-(2-{[3-(trifluoromethyl)phenoxy]methyl}phenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-[2-(phenoxymethyl)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-{2-[(2-methylphenoxy)methyl]phenyl}-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-[2-(furan-2-yl)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-(2-hydroxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-[2-(tetrahydrofuran-3-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-[2-(cyclopentylmethoxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-[2-(tetrahydrofuran-2-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-[2-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-{2-[2-(morpholin-4-yl)ethoxy]phenyl}-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-[2-(pyridin-2-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-[2-(quinolin-8-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-[2-(1-benzothiophen-7-ylmethoxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-[2-(pyridin-3-ylmethoxy)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-[2-(1H-indazol-5-ylmethoxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-(5-amino-2-phenoxyphenyl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;N-[3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamide;N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamide;N-[3-(2,3-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]acetamide;1-[5-amino-2-(phenylsulfanyl)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;N-[3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-(phenylsulfanyl)phenyl]methanesulfonamide;1-[5-amino-2-(2,4-difluorophenoxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]methanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]ethanesulfonamide;N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]-2,2,2-trifluoroethanesulfonamide;N′-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]-N,N-dimethylsulfuricdiamide;N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]acetamide;N-[4-(2,4-difluorophenoxy)-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]-1H-pyrrole-2-carboxamide;N-{4-[(4,4-difluorocyclohexyl)oxy]-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl}ethanesulfonamide; methyl3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxybenzoate;3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxybenzoicacid;N-ethyl-3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxybenzamide;3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxy-N-(tetrahydrofuran-2-ylmethyl)benzamide;3-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxy-N-(1,3-thiazol-2-yl)benzamide;3,6,6-trimethyl-1-phenyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-(2,5-dimethylphenyl)-3,6,6-trimethyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;3,6,6-trimethyl-1-[2-(morpholin-4-yl)phenyl]-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-[2-(benzyloxy)phenyl]-3,6,6-trimethyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;3,6,6-trimethyl-1-(2-phenoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;N-[3-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)phenyl]methanesulfonamide;3,6-dimethyl-1-(2-phenoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-(5-amino-2-phenoxyphenyl)-3,6-dimethyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;N-[3-(3,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamide;3-methyl-6-(2-methylpropyl)-1-(2-phenoxyphenyl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;N-{3-[3-methyl-6-(2-methylpropyl)-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl]-4-phenoxyphenyl}methanesulfonamide;3-methyl-1-(2-phenoxyphenyl)-6-(propan-2-yl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;N-{3-[3-methyl-4-oxo-6-(propan-2-yl)-4,5,6,7-tetrahydro-2H-isoindol-1-yl]-4-phenoxyphenyl}methanesulfonamide;N-[3-(3-methyl-4-oxo-6-phenyl-4,5,6,7-tetrahydro-2H-isoindol-1-yl)-4-phenoxyphenyl]methanesulfonamide;and1-[2-(cyclopropylmethoxy)-5-(methylsulfonyl)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.26. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein said compound is selected from the group consisting of:1-(1,3-benzodioxol-5-yl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-[2-(benzyloxy)phenyl]-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;3-methyl-1-(naphthalen-1-yl)-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-(1H-benzimidazol-4-yl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;1-(1H-indol-7-yl)-3-methyl-2,5,6,7-tetrahydro-4H-isoindol-4-one;2-[2-(3-methyl-4-oxo-4,5,6,7-tetrahydro-2H-isoindol-1-yl)benzyl]-1H-isoindole-1,3(2H)-dione;and1-(1,3-benzodioxol-5-yl)-3,6,6-trimethyl-2,5,6,7-tetrahydro-4H-isoindol-4-one.27. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) according to claim 1, or apharmaceutically acceptable acceptable salt thereof, in combination witha pharmaceutically acceptable carrier.
 28. A method for treating adisease in a subject comprising administering a therapeuticallyeffective amount of a compound of formula (I) according to claim 1, or apharmaceutically acceptable acceptable salt thereof, to a subject inneed thereof, wherein said disease is selected from a disease in one ofthe following groups which consist of: cancer; Addison's disease, acutegout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease,bullous skin diseases, chronic obstructive pulmonary disease (COPD),Crohn's disease, dermatitis, eczema, giant cell arteritis,glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease,Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis,myositis, nephritis, organ transplant rejection, osteoarthritis,pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primarybiliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis,scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus,Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes,ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener'sgranulomatosis; diabetic nephropathy, hypertensive nephropathy,HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgAnephropathy, focal segmental glomerulosclerosis, membranousglomerulonephritis, minimal change disease, polycystic kidney diseaseand tubular interstitial nephritis; ischemia-reperfusion induced kidneydisease, cardiac and major surgery induced kidney disease, percutaneouscoronary intervention induced kidney disease, radio-contrast agentinduced kidney disease, sepsis induced kidney disease, pneumonia inducedkidney disease, and drug toxicity induced kidney disease; AIDS; obesity;type II diabetes; and obesity, dyslipidemia, hypercholesterolemia,Alzheimer's disease, metabolic syndrome, hepatic steatosis, type IIdiabetes, insulin resistance, diabetic retinopathy and diabeticneuropathy.
 29. The method of claim 28 wherein the cancer is selectedfrom the group consisting of: acoustic neuroma, acute leukemia, acutelymphocytic leukemia, acute myelocytic leukemia (monocytic,myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocyticand promyelocytic), acute t-cell leukemia, basal cell carcinoma, bileduct carcinoma, bladder cancer, brain cancer, breast cancer,bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma,choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronicmyelocytic (granulocytic) leukemia, chronic myelogenous leukemia, coloncancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,diffuse large B-cell lymphoma, dysproliferative changes (dysplasias andmetaplasias), embryonal carcinoma, endometrial cancer,endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia,esophageal cancer, estrogen-receptor positive breast cancer, essentialthrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germcell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chaindisease, hemangioblastoma, hepatoma, hepatocellular cancer, hormoneinsensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lungcancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblasticleukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung,ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies ofT-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midlinecarcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oralcancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillaryadenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera,prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma,rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skincancer, small cell lung carcinoma, solid tumors (carcinomas andsarcomas), small cell lung cancer, stomach cancer, squamous cellcarcinoma, synovioma, sweat gland carcinoma, thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer andWilms' tumor.
 30. The method of claim 28 or 29, further comprisingadministering a therapeutically effective amount of at least oneadditional therapeutic agent.
 31. A method of contraception in a malesubject comprising administering a therapeutically effective amount of acompound of formula (I) according to claim 1 or a pharmaceuticallyacceptable acceptable salt thereof, to a subject in need thereof.